Metastatic Brain Tumors

Conservative estimates indicate that there are about 170,000 new cases of metastatic brain disease each year in the United States,¹⁹ and it has been suggested that there may be as many as 500,000.²⁰ This means that brain metastases are the most common intracranial tumors, outnumbering primary brain tumors by more than 10 : 1.²¹ Twenty percent to 40% of patients with systemic cancer will develop metastatic brain disease; 30% to 40% of these patients will present with a single brain metastasis, and the remaining 60% to 70% will present with multiple brain metastases.²² It has also been suggested that the incidence of brain metastases is increasing, owing in part to earlier diagnosis and more effective treatment of primary neoplastic disease, often with chemotherapeutic agents that do not effectively cross the blood-brain barrier, and to the rising incidence of lung cancer, the most common primary source of brain metastases.²³

The primary goal in the management of metastatic brain disease is palliation of debilitating neurological symptoms to attain an optimal combination of duration and quality of life. The median survival of patients with metastatic brain disease is a dismal 1 month without intervention. Corticosteroid therapy generally produces rapid palliation of symptoms, which are usually primarily attributable to peritumoral vasogenic edema, but extends median survival to only 2 months.²⁴ Whole-brain fractionated external-beam radiotherapy (WBRT), generally administered to a total dose of 30 Gy in ten 3-Gy fractions,²⁵ further extends median survival to 4 to 6 months,^26–28 but at least half of all patients treated with this modality ultimately die from progression of their metastatic brain disease.⁸ Two landmark studies in the early 1990s proved that for patients with a single resectable brain metastasis and good neurological performance status, the addition of microsurgical resection to WBRT significantly extends survival,^7,29 and a recent prospective randomized trial demonstrated comparable outcome with the addition of SRS to WBRT.²²

The use of SRS for metastatic brain disease was first described in the late 1980s.^30,31 Since that time, tens of thousands of patients with metastatic brain tumors have been treated with both linear accelerator (LINAC)-based and Gamma Knife (GK) SRS, and both platforms have proved safe and effective.^22,32 SRS is well suited for the treatment of brain metastases. It is minimally invasive and does not require general anesthesia, making it a viable option for patients who cannot tolerate surgery, and it is generally performed as an outpatient procedure. Metastatic tumors are typically spherical, clearly defined lesions on neuroimaging because of contrast uptake, facilitating treatment planning, and are frequently small and histologically well defined, justifying the rapid fall-off of radiation dose at the periphery of the target volume generated by SRS.³³ SRS is readily applicable to lesions located nearly anywhere in the brain, including eloquent locations and deep brain locations^34,35 that would be difficult or impossible to access surgically with acceptable morbidity, and can be used to treat multiple lesions in a single treatment session.^36–43 It has proved to be an effective treatment even for melanoma, sarcoma, and renal cell carcinoma metastases—lesions traditionally considered radioresistant.^38,44–51 SRS may also be used in combination with WBRT, surgery, or both, and may be repeated when necessary to treat recurrent disease.^{38,42,52–54} Additionally, SRS has been shown to be more cost-effective than surgery.^55,56

Like all treatment modalities, SRS has disadvantages as well. It is incapable of rapidly resolving symptoms due to tumor mass effect, and surgical resection is generally a more appropriate treatment for patients with symptomatic mass effect. SRS also has limited applicability for large metastatic lesions (≥3 cm in diameter), owing to increasing radiation exposure to normal brain with increasing target volume,⁵⁴ and for lesions located within close proximity of structures with low radiation tolerance, such as the optic nerves and chiasm.⁵⁷

Multiple large radiosurgical series report median survival in a range from about 7 to 13. 5 months,^{21,36,38,40,43,45,52,58–78} and 1- and 2-year survival probabilities typically range from 31% to 53% and 13% to 30%, respectively.^{21,41,45,59,65,67,71,79,80} Many of these series were limited to solitary brain metastasis,^59,62,68,70 excluded patients with large tumor volumes,^38,45,67 or excluded patients with unfavorable characteristics.^38,58,59,63 Local control values have also been reported in large series, and rates typically range from 82% to 96%,* and 1- and 2-year local control probabilities typically range from 64% to 91% and 46% to 77%, respectively.† Treatment paradigms vary from center to center, and care is generally individualized based on known prognostic factors. Numerous studies have found younger age (usually <65 years),^36,58,85 higher Karnofsky performance score (KPS, usually ≥70)^{21,42,64,66,68,73,85–87} controlled primary tumor,^{40,60,86,88,89} absence of systemic metastatic disease,‡ and asynchronous presentation of brain metastases^66,90 to be significantly associated with improved survival. Many have also found Radiation Therapy Oncology Group (RTOG) Recursive Partitioning Analysis (RPA) class,⁹¹ a composite of age, KPS, primary tumor status, and status of systemic metastatic disease, to be highly correlated with survival (Table 258-1).^{36,40,41,44,53,65}

Currently, the optimal role of SRS in the management of metastatic brain disease is not well defined. Results of the first prospective randomized trials of WBRT with or without SRS have only recently been reported,^22,92 and although they have shown that SRS offers a significant survival benefit for patients with a single brain metastasis, they have not corroborated a large body of retrospective literature suggesting that SRS similarly improves survival for patients with multiple brain metastases.^36,40,43 Although large SRS series consistently report survival durations comparable to those reported in surgical series, no randomized prospective comparison of these two treatment modalities has been conducted.* The available class I data for surgery, WBRT, and SRS in treatment of brain metastases are summarized in Table 258-2 and are discussed in some detail here.

Patients treated with SRS for metastatic brain disease often also receive WBRT. The rationale behind this treatment strategy is the assumption that WBRT will effectively treat micrometastatic foci outside the radiosurgical field, hopefully preventing them from progressing to become detectable, symptomatic brain lesions that may threaten duration and quality of life.⁹⁷ However, there is evidence that the addition of WBRT to SRS is associated with an increased incidence of mild to moderate treatment-related morbidity, and there is concern that WBRT may also cause serious neurological deficit in some long-term survivors.^32,98

Kondziolka and colleagues⁹⁹ reported the results of 104 surveys completed by patients (or their families) treated with SRS with or without WBRT. They found that patients treated with SRS plus WBRT were significantly more likely to report fatigue, concentration problems, short- and long-term memory problems, and disorders of mood compared with patients treated with SRS alone. DeAngelis and associates¹⁰⁰ reported 12 patients cured of brain metastases who developed progressive dementia, ataxia, and urinary incontinence a median of 14 months (range, 5 to 36 months) after treatment with WBRT (total dose of 25 to 39 Gy delivered in 3- to 6-Gy fractions) with or without surgery. They found a 1.9% to 5.1% incidence of WBRT-induced dementia in their study population and estimated that the true incidence is probably higher.

Aoyama and coworkers¹⁰¹ reported the results of the Mini-Mental State Examination (MMSE) in 110 patients who were evaluated as part of a prospective randomized study of patients with one to four brain metastases, who were treated with either SRS alone or with SRS and WBRT. The average baseline MMSE did not differ significantly between treatment groups, but there was a significantly lower score in patients with tumor volume larger than 3 cm³, more edema, and lower KPS (70 to 80 versus 90 to 100). Ninety-two patients underwent follow-up MMSE, and of these, 39 had initial scores of less than 27. Of these patients, 9 of the 17 in the SRS plus WBRT group and 11 of the 22 in the SRS alone group improved by 3 points or more. Deterioration of the MMSE by 3 points or more occurred in 26 patients, and mean time to deterioration was significantly longer for the SRS plus WBRT group (13.6 months) compared with the SRS alone group (6.8 months). The authors attributed this to tumor recurrence in the SRS group and concluded that neurocognitive function most closely correlated with tumor burden and tumor control. They could not, however, comment on long-term neurocognitive effects of the WBRT and stated that they may not be negligible.

Chang and colleagues¹⁰² reported a prospective series of 15 patients treated with SRS alone for one to three brain metastases, and followed them with baseline neurocognitive evaluations that were repeated every 20 to 40 days for 1 year. Nine of the patients had impairment at baseline, and of the five who survived for more than 200 days, four had improved or stable learning and memory, three had improved executive function, and three had improved dexterity. The authors concluded that SRS alone was a safe therapy but that randomized studies with more patients were indicated. As primary treatment of metastatic brain disease continues to become more and more effective, the same patients who will benefit most from freedom from new brain metastases will be at the greatest risk for developing long-term treatment-related morbidities. Accordingly, many studies have sought to better define the effect of WBRT on survival, local control, and regional control following SRS.

Andrews and coworkers²² recently reported the phase III results of RTOG protocol 9508, the first prospective, randomized trial of WBRT with or without SRS for the treatment of metastatic brain disease to reach full accrual. Three hundred thirty-one patients with one to three newly diagnosed brain metastases, KPS score of 70 or higher, and no history of WBRT were randomly allocated to either WBRT alone (167 patients) or WBRT followed by an SRS boost (164 patients). Analysis revealed a significant survival advantage for patients with a single brain metastasis treated with WBRT plus SRS rather than WBRT alone (median survival, 6.5 months versus 4.9 months) but failed to reveal a similar advantage for patients with two to three brain metastases. However, all patients in the WBRT plus SRS group were significantly more likely to have a stable or improved KPS 6 months after treatment and were less likely to be dependent on corticosteroids than those treated with WBRT alone. Multivariate analysis revealed RPA class I and non–small cell lung primary tumor to be significantly associated with improved survival. Analysis also revealed significantly better 1-year local control of lesions treated with WBRT plus SRS compared with those treated with WBRT alone (82% versus 71%). The authors concluded that the addition of SRS to WBRT should be standard treatment for patients with a single brain metastasis and considered for patients with two to three brain metastases.

Kondziolka and colleagues⁹² had previously conducted a similar randomized prospective study, in which patients with two to four brain metastases and KPS of 70 or greater were randomly allocated to either WBRT alone or WBRT plus SRS; however, this study was stopped at an interim evaluation (60% accrual: 14 patients in the WBRT alone group and 13 in the WBRT plus SRS group) because detection of significantly better local control following WBRT plus SRS compared with WBRT alone. Median time to local failure was 6 months after WBRT alone compared with 36 months after WBRT plus SRS, and 1 year after treatment, no patient in the WBRT group had maintained local control, compared with 92% of patients in the WBRT plus SRS group. Although interim analysis revealed a trend toward improved survival after WBRT plus SRS compared with WBRT alone (median survival durations of 11 months and 7.5 months, respectively), no conclusions could be made owing to the small number of patients in the study.

Aoyama and associates¹⁰³ recently reported results of the first prospective, multi-institutional, randomized trial of SRS with or without WBRT for the treatment of metastatic brain disease. One hundred thirty-two patients with one to four brain metastases 3 cm or less in diameter and KPS of 70 or greater were randomly allocated to either SRS plus WBRT (65 patients) or SRS alone (67 patients). Adjuvant WBRT did not affect survival; patients who received both SRS and WBRT had a median survival of 7.5 months and a 1-year actuarial survival rate of 38.5%, compared with 8.0 months and 28.4% for those treated with SRS alone. However, patients who did not initially receive WBRT underwent significantly more salvage procedures. Multivariate analysis revealed age younger than 65 years, controlled primary tumor, stable systemic disease, and KPS of 90 or greater to be significantly associated with improved survival. Analysis revealed significantly better local, regional, and total brain control after treatment with SRS plus WBRT compared with SRS alone. Patients treated with SRS plus WBRT had 1-year actuarial local control, regional control, and total brain control rates of 88.7%, 58.5%, and 53.2%, respectively, compared with 72.5%, 36.3%, and 23.6%, respectively, for patients treated with SRS alone. Multivariate analysis also revealed stable systemic disease and KPS of 80 or greater to be significantly associated with improved regional control, and a single brain metastasis approached significance (P = . 06). Analysis revealed no difference in posttreatment neurological performance; patients treated with SRS plus WBRT had a 1-year actuarial neurological preservation rate of 72.1%, compared with 70.3% for patients treated with SRS alone. These findings are consistent with the only prospective, randomized trial to date on the role of postoperative WBRT in the management of metastatic brain disease, in which Patchell and colleagues⁹⁵ randomized 95 patients with a single resectable brain metastasis and KPS of 70 or greater to surgery plus WBRT or surgery alone and determined that patients who received postoperative WBRT did not have a survival advantage but did have significantly better local, regional, and total brain control.

Two similar randomized prospective trials of SRS with or without WBRT for the treatment of metastatic brain disease are underway. North Central Cancer Treatment Group (NCCTG) protocol N0574 will randomize 528 patients with one to three newly diagnosed brain metastases to treatment with SRS plus WBRT or SRS alone. Primary outcome will be duration of survival; secondary outcomes will be time to central nervous system failure, quality of life, duration of functional independence, long-term neurocognitive status, and posttreatment toxicity.¹⁰⁴ This trial is a continuation of American College of Surgeons Oncology Group (ACOSOG) protocol Z0300, which was inactive following suspension of enrollment in December 2004.¹⁰⁵ European Organisation for Research and Treatment of Cancer (EORTC) protocol 22952-26001 will accumulate 340 patients with one to three newly diagnosed brain metastases. One hundred seventy of these patients will have undergone complete surgical resection and will then be randomized to postoperative WBRT or no postoperative WBRT. The other 170 patients will be randomized to SRS plus WBRT or SRS alone. Primary outcome will be duration of survival with a World Health Organization performance status of 2 or greater; secondary outcomes will be duration of survival, duration of progression-free survival, time to neurological progression, acute toxicity, late toxicity, and quality of life.¹⁰⁶

Another study that falls into this category for patients with a single brain metastasis was recently published by Muacevic and associates¹⁰⁷ comparing surgery followed by WBRT with SRS alone. This was a prospective randomized trial consisting of 64 patients: 33 in the surgery group and 31 in the SRS group. Median survival for the two groups was not significantly different, with 9.5 months for the surgery group and 10.3 months for the SRS alone patients. Local control at 1 year was 82% for surgery and 96. 8% for SRS, again a nonsignificant difference. Regional control was significantly better in the surgery group, with 97% of patients free from distant metastases at 1 year, compared with 74.2% of the SRS group. These authors concluded that SRS and surgery provided similar local control, but WBRT significantly improved control of distant metastases. Rades and colleagues⁷⁹ reported on a retrospective analysis of patients with one or two brain metastases treated with SRS alone or with surgical resection plus WBRT. There were 94 patients in the SRS group and 112 in the surgical group. These authors found no significant differences between the groups in terms of overall survival, local control, and regional control. There was no evaluation of cognitive function or quality of life.

The role of repeat SRS compared with WBRT as an upfront therapy remains an unanswered question. Because of the current paucity of class I data, several groups have conducted matched nonrandomized prospective and retrospective studies of SRS with or without WBRT for metastatic brain disease. They have consistently determined that the addition of WBRT to SRS does not affect survival but may affect local and regional control.^32,74,98,108 Results of this nature have led some authors to conclude that it may be best to initially employ SRS as a monotherapy and reserve WBRT for possible salvage treatment.^{61,64,82,99,102,109} Many centers often employ repeat SRS in lieu of WBRT for salvage treatment,⁵² and newer reports exist of radiosurgical boost to the resection cavity after surgery alone, also in lieu of WBRT.¹¹⁰

This vast experience and repository of data for SRS for brain metastases proves that SRS is safe and effective for the treatment of brain metastases, specifically in patients with a single metastasis. Further class I studies to determine the best use of SRS in patients with multiple tumors and the need for WBRT are ongoing. We hope these will answer questions regarding the optimal combination of SRS, open surgery, and WBRT in treating this rapidly increasing patient population.

Anaplastic Astrocytoma and Glioblastoma

Most of the reported experience with SRS to treat primary intrinsic brain tumors has been for patients with malignant astrocytomas. Primary brain tumors are by nature more infiltrative and are more difficult to target as separate from normal brain, and thus SRS for these lesions would not seem optimal. However, in the case of malignant gliomas, radiation therapy (RT) is the most effective management tool, and overall survival appears to be correlated with the total dose delivered, up to a total dose of 60 Gy.^111,112 Also, most tumor recurrences occur within 2 cm of the enhancing margin of the original tumor, leading to the postulate that increasing dose to this area may improve survival and progression-free survival.^113,114 This realization led to the initial interest in and use of interstitial brachytherapy for the treatment of malignant gliomas.¹¹⁵ In this technique, radio-isotopes, usually iodine-125, are implanted directly into the tumor cavity after resection to provide maximal radiation dose to the surrounding tissue. Early evidence in the 1990s appeared to show that brachytherapy increased survival in brain tumor patients.¹¹⁵ However, since that time, three separate clinical trials, most recently in 2007, have shown no evidence of a survival benefit, and an increased risk for radiation necrosis, toxicity, and reoperations,^116–118 and it became clear that selection bias led to the erroneous conclusion that brachytherapy had a positive treatment effect.

Likewise, in the 1990s, reports appeared to show good efficacy and increased survival benefit with the use of SRS at the time of surgical resection in conjunction with conventional radiotherapy and chemotherapy (Table 258-3).^119–148 However, this survival benefit may have been more related to patient selection than actual treatment effect.¹⁴⁹ Similar to the experience with brachytherapy, selection bias is likely to have been the driving force behind the apparent efficacy of SRS in these early reviews.

To eliminate the problem of selection bias, the RTOG 93-05 protocol was established for a randomized comparison of SRS followed by conventional RT and carmustine (BCNU) chemotherapy compared with conventional RT and BCNU chemotherapy alone.¹⁴¹ A total of 203 patients with supratentorial glioblastoma (GBM) smaller than 40 mm were randomized to receive SRS plus RT (60 Gy) and BCNU or RT and BCNU alone. SRS dose ranged from 15 to 24 Gy depending on tumor size. At a median follow-up of 61 months, patients had a median survival of 13.5 months in the SRS group compared with 13.6 months in the conventional treatment group. The data were also analyzed to determine whether there was a tail effect, leading to more long-term survivors, but 2- and 3-year survival rates were not significantly different. Recurrence patterns, cognitive decline, quality of life, and type of SRS used (GK or LINAC) were also analyzed and did not show significant differences. The results of this trial proved that upfront SRS is not of benefit for patient survival or quality of life, and prior reports of efficacy were likely due to selection bias.