Expanding Indications for Stereotactic Radiosurgery in the Treatment of Brain Metastases

Friedman, William A. MD

doi: 10.1227/01.neu.0000430329.25516.94

Surgical neuro-oncology tends to be focused on primary brain tumors (those originating within the cranium). However, each year in the United States, only 20 000 new primary brain tumors are diagnosed. In contrast, > 200 000 new metastatic brain tumors are seen annually. The most common primary tumors are lung, breast, kidney, gastrointestinal, and melanoma. Twenty percent to 40% of all cancer patients will develop a metastatic brain tumor sometime during the course of their illness. These tumors will be multiple 60% to 70% of the time; the remainder are solitary. The overall incidence of brain metastases is increasing, probably because treatment of the primary tumors has improved, leading to longer life expectancies and hence longer times during which a brain metastasis can develop.

Historically, the treatment of metastatic brain tumors has been very nihilistic. Best supportive care leads to a very short survival (1-2 months). Steroids may produce significant palliation of symptoms by reducing edema, but this effect is generally short lived. Whole-brain radiotherapy (WBRT) has been the mainstay of treatment for several decades, improving survival to the 6-month range. Surgery has been used primarily for solitary lesions or lesions presenting with significant mass effect. In the past decade, stereotactic radiosurgery (SRS) has become a popular alternative.

As one might imagine, there is significant controversy concerning the optimal application of the available treatment modalities: surgery, WBRT, and SRS. Here, I review the best evidence in the literature for the various combinations of these treatments. I review the University of Florida experience with SRS, and I will conclude with my interpretation of the available data.

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In 1990, Patchell and colleagues1 published a groundbreaking study comparing the results of WBRT alone against WBRT and surgery. Median survival time, functional independence time, and incidence of local recurrence were all better with the combination therapy. In 1993, Vecht et al2 reached similar conclusions. Mintz et al,3 in 1996, did not. Since that time, many solitary brain metastases have been treated with this particular combination of therapies (Table 1).

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In 1998, Patchell et al4 looked at 95 patients with solitary brain metastases treated with surgery alone or surgery plus WBRT. Interestingly, the surgery alone group had 54% local control, implying that surgery alone could cure about half of these tumors. Combination therapy again produced a much higher local control rate (90%) and a much lower neurological death rate (14%). In 2008, Muacevic et al5 found in 64 patients that surgery produced 74% overall control at 1 year, whereas surgery and WBRT produced 97% overall control at 1 year (Table 2).

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If surgery with WBRT is superior to WBRT alone or surgery alone, could the surgical part be replaced with radiosurgery? Four studies have addressed that question (Table 3). One study (Rades et al6 in 2009) showed improved 1-year survival, intracranial control, and local control with radiosurgery replacing surgery. The other 3 studies7-9 showed no significant difference between the 2 arms. This suggests that radiosurgery can replace surgery, at least for tumors with no substantial mass effect.

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Seven studies10-16 have addressed the question of 1 monotherapy (SRS) vs another (WBRT; Table 4). All but 1 study (Datta et al16) showed superiority of SRS over WBRT in terms of 1-year survival, local control, and intracranial control. This suggests that the doses of radiation used in the typical WBRT paradigm (300 cGy per day times 10 days) are too low to produce tumor control. This is likely especially true for radioresistant histologies like melanoma and hypernephroma.

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Two studies have addressed this issue (Table 5). Aoyama et al17 found that 1-year overall recurrence was better with the addition of WBRT, but median survival and neurological death rate were not different. Chang et al18 found that all end points, including 1-year survival, 1-year local control, 1-year distant control, and 1-year overall control, were significantly better with the addition of WBRT. This is an intuitively congruous finding: SRS treats only the local disease; it cannot prevent other metastases in other brain areas. The addition of WBRT provides more radiation, even to the lesion treated by SRS, which should improve local control. These unanswered questions remain: Will WBRT produce general brain injury, leading to cognitive decline? Can SRS, followed by repeat SRS for new lesions, produce equivalent or better tumor control without cognitive decline? Can WBRT be used as a salvage treatment later, or does it need to be given upfront?

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We undertook a retrospective review19 of all patients treated between May 1989 and February 2006. There were 619 patients, 745 treatments, and 1569 lesions. Median actuarial survival was 7.9 months. Two-year survival was 14%. The addition of WBRT did not significantly improve survival. The 1 factor associated with shorter survival was melanoma histology. For more details, the reader is referred to the original article.19

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1. Surgery plus WBRT is more effective than surgery alone. SRS is more effective than WBRT alone. SRS plus WBRT is more effective than WBRT alone. Therefore, WBRT alone should be reserved for patients with poor prognosis (Karnofsky Performance Scale score < 70, large number of tumors).

2. SRS plus WBRT is at least as effective as surgery plus WBRT for those lesions that do not require urgent surgical resection. SRS is as effective as surgery plus WBRT. Surgery has a higher complication rate than SRS. Therefore, surgery should be reserved for lesions too big for SRS or those lesions causing mass effect symptoms.

3. SRS plus WBRT produced higher local and regional control than SRS alone. However, SRS plus WBRT produces a higher incidence of neurocognitive effects than SRS alone. One might therefore consider SRS followed by salvage SRS as an alternative approach. This is, in fact, what we do at the University of Florida. This has not been evaluated by a randomized controlled trial.

4. Surgery alone appears to cure 50% of metastatic tumors. Both WBRT and SRS can cause complications. Therefore, one may consider magnetic resonance imaging follow-up after surgery for solitary metastases, reserving radiation treatment for definitive recurrence. That radiation treatment could be SRS or WBRT.

For related video content, please access the Supplemental Digital Content: http://www.youtube.com/watch?v=zr8doxCenwM

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The author has no personal financial or institutional interest in any of the drugs, materials, or devices described in this article.

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Daniel Neal, MS, biostatistician, and Barbara Frentzen, ARNP, MSN, provided valuable help with the tables and references.

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