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Stereotactic Radiosurgery for Brain Metastases
Authors and Disclosures
Michael L. Smith, M.D., John Y. K. Lee, M.D., University of Pennsylvania Health System, Department of Neurosurgery, Philadelphia, Pennsylvania
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Abstract and Introduction
Stereotactic Radiosurgery for Brain Metastases
Stereotactic Radiosurgery Technique
Dose and Tumor Size
Radioresistance and Radiosensitivity to SRS
Complications of SRS
Craniotomy Compared with SRS
Is WBRT Needed After SRS?
Which SRS System is Best?
Conclusions
Abstract and Introduction
Abstract
Metastatic disease to the brain occurs in a significant percentage of patients with cancer and can limit survival and worsen quality of life. Glucocorticoids and whole-brain radiation therapy (WBRT) have been the mainstay of intracranial treatments, while craniotomy for tumor resection has been the standard local therapy. In the last few years however, stereotactic radiosurgery (SRS) has emerged as an alternative form of local therapy. Studies completed over the past decade have helped to define the role of SRS. The authors review the evolution of the techniques used and the indications for SRS use to treat brain metastases. Stereotactic radiosurgery, compared with craniotomy, is a powerful local treatment modality especially useful for small, multiple, and deep metastases, and it is usually combined with WBRT for better regional control.
Introduction
Brain Metastasis is the most common intracranial tumor, with an estimated annual incidence of more than 100,000 cases.[44] In 20 to 40% of patients with cancer, metastatic lesions travel to the brain.[8,44] On the basis of historical studies, medical treatment with glucocorticoids alone yields a life expectancy of less than 3 months. The addition of WBRT improves survival to 3 to 6 months.[6,27] Aggressive local treatments such as resection and radiosurgery in combination with WBRT can achieve median survival times of 9 to 12 months in some patients.[2,40]
The RTOG has conducted multiple studies that have helped to delineate several predictive variables for patients with metastatic brain disease. Among the most important predictive factors is the general medical and oncological condition of a patient. Gaspar and colleagues[21] evaluated 1200 patients from previous RTOG studies and used RPA to identify three major variables predictive of outcome: patient age greater than or equal to 65 years, functional independence as defined by a KPS score greater than or equal to 70, and controlled compared with uncontrolled extracranial disease. The authors then stratified the patients into RPA Classes 1, 2, or 3 according to these variables. The single most important predictor of out come was functional status, and patients with KPS scores less than 70 (RPA Class 3) had the worst prognosis. Young and functionally independent patients with controlled extracranial disease (RPA Class 1) had the best prognosis ( Table 1 ).
Although RPA class is the most important predictor of survival, aggressive local therapy (such as resection) for metastatic foci in addition to regional therapy (WBRT) improves survival in selected patients.[35,40] In a surgical trial conducted at a single medical center in the United States, Patchell et al.[40] randomly assigned 48 patients with single brain metastases to two treatment groups and demonstrated a median survival of 40 weeks in the patients that underwent resection and WBRT compared with 15 weeks in patients who underwent WBRT alone. Similarly, Noordjik and coworkers[35] showed a statistically significant survival advantage in their European study of patients with single brain metastases who underwent resection. One study of 83 patients failed to prove a survival benefit in patients who underwent resection.[31] The lack of benefit in this last study has been attributed to the overwhelming influence of RPA class on survival, especially in terms of control of extracranial disease. Patient selection is crucial, therefore, to realizing benefit from aggressive local management of patients with brain metastasis.
Stereotactic Radiosurgery for Brain Metastases
Because of the success of aggressive local control with resection for a single metastasis, neurosurgeons have pursued a complementary approach with the use of SRS to control single and multiple brain metastases. In a relatively short time, SRS has emerged as an important noninvasive option in the neurosurgical armamentarium against brain metastasis. Brain metastases are discrete and often semispherical, thus making attractive radiosurgical targets.
The largest and most influential study conducted to date in patients with brain metastasis treated with SRS comes from RTOG 95-08 by Andrews and colleagues.[2] This was a multiinstitutional clinical trial in which 333 patients were randomly assigned to two treatment groups. The patients in one group underwent both SRS and WBRT and those in the other group underwent WBRT alone. Study inclusion criteria were the presence of one to three brain metastases, patient age older than 17 years with no history of previous cranial irradiation, and a KPS score greater than 70. In contrast to the patients who participated in the studies of resection alone, patients with multiple brain metastases (one to three lesions) were eligible to participate. The primary end point was survival. Two major groups of patients benefitted from radiosurgery: those with a single metastasis (regardless of RPA class) and those in RPA Class 1 with up to three brain metastases. An intent-to-treat analysis was used to control for both known and unknown biases. It is important to note that 31 of 164 patients assigned to the SRS group did not actually undergo SRS, and 28 of 167 patients in the WBRT arm received salvage SRS. Hence, a "per protocol" analysis probably would have demonstrated an even greater survival advantage for the same groups. On the basis of this randomized trial, SRS has been established as an important tool in the local management of brain metastasis.
In an earlier randomized clinical trial, Kondziolka et al.[24] examined local control as the primary end point in their study of patients with multiple metastases. The authors compared local control in patients with two to four metastases who underwent either WBRT alone or WBRT and SRS. The study was stopped after 60% accrual because the interim analysis showed a dramatic advantage to adding SRS.[24] Median time to local failure was 6 months in patients who received WBRT alone and 36 months in patients who received both WBRT and SRS. Because the study was stopped early, the survival difference between the two groups was not statistically significant. Nevertheless, the authors demonstrated that SRS improves local control.
Stereotactic Radiosurgery Technique
Stereotactic radiosurgery is performed with either a LINAC or a Co-60 gamma source unit. Masks or cranial pin frames provide immobilization. Regardless of technique, preoperative imaging is paramount. Gadolinium-enhanced T1-weighted MR imaging is standard. Contrast-enhanced computed tomography scans can be used if MR imaging is not possible. Tailored MR imaging techniques are available to increase detection of small and emerging metastases. Triple-dose Gd and MT magnetization transfer can be used to detect lesions not seen on single-dose images.[54] Triple-dose imaging can help clarify any equivocal findings on single-dose imaging, but it is more expensive, is time consuming, carries an increased false-positive rate, and is probably not justified for routine use.[53
Dose and Tumor Size
Radiation dosing is usually described in terms of Gy delivered to the prescription isodose line. This allows a simple understanding of the minimum amount of radiation delivered to every tumor cell. The prescription dose refers to the radiation dose, usually specified in Gy or cGy, delivered to the tumor margin. Hence, the general goal is to include the entire gross tumor volume within the prescribed tumor volume. The prescription dose is often referenced as a percentage of the maximum dose (Fig. 1). To achieve effective local control and the survival benefit of SRS requires the delivery of a tumoricidal radiation dose to all neoplastic cells within the prescription dose line while minimizing the radiation dose to the surrounding brain parenchyma. Modern SRS systems can contour isodoses to the tumor volume precisely, but large tumor volumes present difficulties. A large tumor volume results in a higher integral radiation dose to the surrounding brain. Thus, larger tumors must generally be treated with a lower dosage in order to avoid radiation toxicity.[46] Because of the corresponding decrease in dose, the ability to achieve local control may be compromised.
Figure 1.
Screen snapshot from planning software showing targeting of a left thalamic enhancing mass in a patient with metastatic melanoma. Two prescription isodose curves show 50% (yellow) and 35% (green).
Dose escalation studies conducted by the RTOG outlined maximum tolerated doses in patients undergoing SRS after WBRT or fractionated external-beam radiation.[46] The study population included patients with primary gliomas and brain metastases and was not subdivided. The primary stratification variable was size. The tumors were divided into groups of less than 2 cm, 2 to 3 cm, or 3 to 4 cm ( Table 2 ). The maximum tolerated dose was not reached for tumors larger than 2 cm. This study provides a guideline for dosing but does not account for other variables, such as location of delivery. For example, the optic nerve and brainstem are more sensitive to radiation-induced edema than the frontal lobe.[19] The dose prescription must be reduced if necessary to protect such structures. Clinical judgment and experience remain important in dose prescription.
The authors of several studies have demonstrated differences in local tumor control based on size. One study demonstrated a 78% response rate in tumors 2 cm3 or smaller compared with a 50% response rate in tumors 10 cm3 or greater.[22] In a study of 103 patients with melanoma metastases, local control rates after SRS were 75.2% for lesions less than 2 cm in diameter compared with 42.3% in larger lesions.[45] The same authors studied another 135 patients with tumors of various histological types and found local 1- and 2-year control rates of 86 and 78% for tumors less than 1 cm in diameter compared with 56 and 24% for tumors of larger diameters.[9] A systematic analysis of this topic comes from a recent publication in which the established dosing schedule outlined by RTOG 90-05 was used.[53] A three-part grouping of 1-year local control rates based on size is presented in Table 2 .
Local control has been used as a surrogate end point in some trials[24] but does not necessarily correlate with survival. Two studies found no significant effect of tumor size on survival,[18,48] whereas another found it to be the most important factor predicting survival.[49]
The size of the brain metastasis must influence the choice of treatment modality. Local control of larger tumors with SRS is compromised because of the need to limit the prescription dose. Larger tumors with mass effect, especially if single and superficial, should be resected if the patient is young, has good systemic disease control, and a high KPS score. Tumors that are small, multiple, deep, or that have a minimal mass effect should be managed with SRS. Clinical judgment and patient preference must help guide treatment decisions for the many patients with conditions between the two extremes.[39]
Radioresistance and Radiosensitivity to SRS
Traditional concepts of radioresistance and radiosensitivity to fractionated external beam radiation may not correlate with the response of brain metastasis to SRS. For example, brain metastases from melanomas and sarcomas have traditionally been considered radioresistant based on their response to WBRT (3 Gy per fraction). In contrast, Mehta et al.[30] evaluated volumetric response rates based on the histological characteristics of the lesions. They found complete response to treatment in 100% of lymphomas, 67% of melanomas and sarcomas, 50% of non-small cell lung cancers, 33% of breast cancers, and 11% of renal cell carcinomas. Again, tumor stabilization or shrinkage noted radiologically did not correlate with clinical outcome. Patients with more radioresistant tumor types often fared better after SRS than those with radiosensitive types. In a multiinstitutional review, patients with melanomas, breast cancer, and renal cell carcinomas treated with SRS survived longer than patients with other lesion types.[18] In a review of studies assessing radiological regression and local control, Boyd and colleagues[7] noted that traditionally radiosensitive tumors did show more complete radiographic regression than the radioresistant tumors. However, clinically relevant local control rates were as good or better for the "radioresistant" types as the "radiosensitive" types.[7]
The deviation of SRS responses from the traditional definition of radiation resistance may have to do with the different mechanism of killing cells compared with fractionated methods.[34,37] This may be due to a different impact on tumor vasculature.[23] A single high dose of radiation delivered by SRS can provide local control for tumors that are resistant to standard radiation therapy.
Complications of SRS
Reported complications of SRS include peritumoral edema, radiation-induced necrosis, tumoral hemorrhage, and radiation-induced neoplasia. In a review of 264 brain metastases treated in 189 patients, Chang and coworkers[10] reported a 6.4% rate of hemorrhage within 2.5 months of treatment with SRS. In half of these cases of hemorrhage corrective surgical treatment was required. The authors also noted a 3.8% rate of significant peritumoral edema, and in half of these cases, too, the patients had to undergo resection. The study by Chang et al. included renal cell carcinomas, melanomas, and sarcomas only.
Lutterbach et al.[26] evaluated responses to treatment with SRS in 101 patients harboring metastases of various histological subtypes and noted complications in 13 patients. Some of these complications occurred within the first month (worsened seizures or transiently worsened neurological deficits) and some arose between 5 and 26 months posttreatment (such as fixed neurological deficits or radiation necroses). Radiation-induced necrosis can be difficult to manage because standard imaging characteristics do not distinguish reliably between necrosis and residual or recurrent tumor at the treatment site. Advanced imaging modalities, such as MR spectroscopy, can help differentiate between the two and may assist in further treatment decisions.[11]
Radiation-induced neoplasia has been described after SRS. Meningiomas have been documented to grow in arteriovenous malformation treatment beds.[47] Malignant progression of benign lesions treated with SRS is another problem, although deciphering treatment effect from natural history can be difficult.[25] Although radiation-induced neoplasia must be considered when recommending SRS for benign tumors or curable vascular lesions, it is less important for patients with brain metastases. These lesions are already malignant, and the patient's life expectancy is short relative to the normal time frame for this complication. One case report describes the development of an anaplastic astrocytoma 5 years after SRS treatment of metastatic melanoma. The authors reiterate the very low incidence of radiation-induced neoplasia after SRS.[28]
Craniotomy Compared with SRS Comparative Efficacy
Resection of a single accessible brain metastasis in addition to WBRT has been the standard of care for single metastases in patients with other favorable prognostic factors. However, SRS is becoming more commonly available and a number of studies have demonstrated efficacy comparable with craniotomy, making the decision as to which is the optimal treatment more complex. Indeed, some authors have even suggested that SRS may supplant craniotomy as the new gold standard.[17]
One obvious disadvantage to SRS is the lack of histological confirmation of diagnosis. Among patients with known systemic cancer and a new brain lesion,[5] up to 11% may be harboring an alternative pathological entity such as a primary brain tumor, abscess, or even a hemorrhage.[13] Resection provides both the treatment and the opportunity for diagnosis. Therefore, resection–or at least biopsy sampling–should be considered for any patient without a clear diagnosis.
Several investigators have initiated randomized controlled trials to compare the efficacy of these two treatments. Patient accrual has been difficult, and the results are not yet available. In place of prospective data, one can try to glean data from the multiple retrospective studies that have been performed. There are three single-center retrospective analyses comparing SRS to craniotomy. Bindal et al.[5] studied 31 retrospectively matched patients treated with SRS and 62 patients treated with craniotomy. These authors found a median survival period of 7.5 months in the SRS group compared with 16.4 months in the craniotomy group (p = 0.0018). This study has been criticized because of an overt selection bias and differences in radiosurgical techniques and outcomes in comparison to other groups. Muacevic et al.[32] retrospectively reviewed 108 patients and compared a group of patients who underwent craniotomy and WBRT compared with those who underwent SRS alone. These authors found no significant difference in 1-year survival, 1-year local control, or morbidity and mortality rates. O'Neill et al.[36] studied 97 patients with single brain metastases, of whom 74 underwent craniotomy and 23 underwent SRS. Their rate of local failure for surgery was unusually high at 58%. None of the SRS patients had local failure. Regardless, they found no difference in 1-year survival.
Several authors have attempted to review the existing literature to determine the role of SRS compared with conventional craniotomy and resection. Sperduto[51] undertook a literature review and reached several conclusions: patients with a single accessible metastasis should undergo craniotomy; patients with one to three tumors and a KPS score greater than 70 should receive both SRS and WBRT; patients with more than three tumors and a KPS score less than 70 should undergo WBRT only. Boyd and colleagues[7] studied 21 reports of SRS for brain metastasis. Although they were unable to perform a definitive analysis due to data inhomogeneity, they found an average local control rate of 83% and median survival of 9.6 months. As noted in their report, this is comparable to the results of recent surgical series. Boyd and colleagues note the following characteristics that make metastasis amenable to SRS: lesion tendency toward spherical shape, gray-white junction location allowing the application of a large radiation dose with minimal toxicity, and frequent presentation at less than 3 cm diameter. In a literature review and commentary, Alexander and Loeffler[1] concluded that SRS is comparable to surgery and therefore surgery should be restricted to the minority of patients for whom the brain metastasis is immediately life threatening.
In summary, there is no confirmed clear advantage of one treatment over the other. The discomfort, risks, and costs of surgery must be justified to recommend this treatment to a patient. The two modalities have some complementary aspects. Stereotactic radiosurgery seems clearly preferable for small, multiple, and deep lesions, and in patients unlikely to tolerate general anesthesia well. Craniotomy should be recommended for single, large lesions causing herniation or a posterior fossa mass effect. For tumors that could reasonably be treated using either modality, patient and physician preference will play a large role and both modalities remain accepted practices.
Cost-effectiveness of SRS
Most studies demonstrate that SRS is a cost-effective treatment for patients with brain metastasis. Mehta et al.[29] undertook a cost-effectiveness analysis of patients with brain metastases, among whom 46 underwent resection, 135 received SRS, and 454 received WBRT alone. The authors found that surgery and SRS were similarly effective and superior to the use of WBRT alone. The net cost of surgery was 1.8-fold higher. The average cost per week of survival was $310 for WBRT, $524 for surgery and WBRT, and $270 for SRS and WBRT.
Rutigliano et al.[42] reviewed the literature on the economic efficiency of SRS or surgery with WBRT from 1974 to 1994 and had similar (although less dramatic) findings, stating the cost as $24,811/life year ($477/week) for SRS combined with WBRT compared with $32,149/life year ($618/week) for craniotomy. Thus, craniotomy is 1.3 times more expensive for the additional survival time offered com pared to 1.8 times more expensive as reported by Mehta et al.
In a Munich study, 127 patients with various diagnoses were treated with craniotomy or SRS. The SRS costs were determined by the global operating costs for the GKS center divided by the number of patients treated. Craniotomy costs included the costs of surgery, the intensive care unit, and inpatient and ancillary services. The costs of treating meningiomas, vestibular schwannomas, brain metastases, and arteriovenous malformations less than 3 cm in diameter averaged 15,242 euros for craniotomy and 7,920 euros for SRS.[56]
Compared with conventional craniotomy, SRS is a cost-effective treatment for brain metastasis. The decision to pursue craniotomy or SRS as a treatment in a particular patient should not be determined by economics. However, because cost, access, and resource management are increasingly important, these factors must be included in professional discussions of treatment algorithms.
Is WBRT Needed After SRS?
Whole brain radiation therapy is an accepted treatment modality for brain metastases. As mentioned, the addition of WBRT improves patient survival from 1 to 2 months to 3 to 6 months after the original diagnosis.[6,27] The community standard regimen is 30 Gy delivered in 10 fractions,[12] although other protocols have been investigated. An RTOG study using hyperfractionation demonstrated improved survival and neurological function.[16] How ever, a follow-up randomized trial in which patients received 1.6 Gy twice a day and 54.4 Gy total could not conclusively show improved survival.[33]
Radiation-induced dementia is a serious side effect of WBRT. This complication occurs 6 to 12 months after irradiation and can be very debilitating.[4,14] This raises the question whether WBRT should be used more judiciously. Patients with good KPS scores are likely to live longer and are more likely to benefit from improved cerebral tumor control but are also more likely to suffer delayed dementia after WBRT.
Aoyama and colleagues[3] recently published a randomized controlled trial of 132 patients with up to four metastases each who underwent SRS or SRS followed by WBRT. The primary end point was survival. Secondary end points included functional preservation and radiation toxicity. The Mini Mental Status Examination was used for assessment. This is a rapid but not thorough neuropsychological tool. Consistent with previous retrospective studies,[20,50] Aoyama and colleagues found that SRS alone does not provide as good local or distant control as SRS with WBRT. The elimination of WBRT did not, however, result in shortened survival or an altered level of functional independence. This is similar to the results of a surgical trial published by Patchell et al.[38] in 1998 in which patients were randomly assigned to groups that received resection with or without WBRT. This study also failed to demonstrate a survival advantage with the addition of WBRT. Neither trial was designed as an equivalency study and should not be interpreted as such. Instead, we can conclude that within the power of the predetermined criteria, both studies failed to show a survival advantage with the addition of WBRT if patients are treated with SRS initially or even with resection.
The major reason for withholding WBRT is to avoid the late onset of radiation-induced dementia. Unfortunately, Aoyama et al.[3] used an effective but perhaps insensitive tool to study functional status–the KPS score. The ability to determine radiation-induced dementia and complications may require a more sensitive measure than KPS score. It remains unproven, although intuitive, that an SRS-only treatment plan would reduce the incidence of radiation-induced dementia.
An alternative strategy for treatment of new brain metastases is SRS alone initially and WBRT given only to those with treatment failure. Sneed et al.[50] concluded that patients with single metastasis are most likely to benefit from WBRT. However, they noted that SRS without WBRT led to salvage (delayed) WBRT in only 26% of their patients, thus sparing 74% the loss of time, the expense, and the risk of dementia.
Deinsbeger et al.[15] studied 110 patients with new brain metastases and found a local control rate of SRS without WBRT of 89.4% and a median survival of 12.5 months. Based on this high rate of control with the single modality, they recommended that WBRT be reserved for cases of numerous metastases or used in a delayed fashion for recurrence. Conversely, Aoyama et al.[3] found a significantly higher need for salvage WBRT in patients who had undergone SRS alone compared with those treated with SRS and WBRT initially.
Further evaluation is needed to clarify the proper use and timing of WBRT in patients treated with SRS. The North Central Cancer Treatment Group Is currently treating patients harboring one to three brain metastases with SRS alone and with SRS followed by WBRT. Overall survival duration, central nervous system control, quality of life, and toxicity are among the end points. Such data from a large study may help the clinician in the future with this decision.
Which SRS System is Best?
There are two fundamental types of SRS systems. The prototype radiosurgical system is the Gamma Knife (Elekta) which uses 201Co-60 sources semispherically arranged around a geometric center. The basic engineering design concepts of the Gamma Knife have not changed since its development in 1967; design changes have increased usability and efficiency. This modality relies on forward planning with the delivery of "shots" to the tumor. It relies on the stereotactic Leksell G frame for rigid skull fixation and accurate dose delivery. The nomenclature "stereotactic radiosurgery" was coined by Lars Leksell, the Swedish neurosurgeon who invented the current Leksell arc-centered frame and the Gamma Knife. The precision and accuracy of GKS remain the standards by which intracranial SRS is defined.
The second type of radiosurgical system is based on linear accelerators, or LINACs, which are standard radiation oncology tools. The radiation source is mounted on a robotic arm and moves around the patient. Such systems include the Cyberknife (Accuray), X-Knife (Radionics), Trilogy (Varian), and Novalis (BrainLab). Early LINAC machines did not have the sophisticated features seen on modern units such as multileaf collimators, reverse planning software, and image-guided capabilities with cone-beam computed tomography scanners. Early versions were imperfectly adapted for precise cranial anatomy, resulting in poor quality assurance and, consequently, poor clinical outcomes compared with GKS.[43,46] Modern LINACs have gained sophistication. Some units allow non-frame-based stereotaxis, using a molded face mask or similar device. This alternative may appeal to patients who wish to avoid cranial pins and is more amenable to hypofractionated treatment regimens. Additionally, extracranial targets (such as spinal lesions) may also be targeted.
Most of the radiosurgical literature does not distinguish between GKS and LINAC SRS. The efficacy and safety of the two modalities are likely similar with the modern systems, although there is clearly a higher central dose, and thus more dose inhomogeneity, with GKS. Depending on the situation, this may serve as either an advantage or disadvantage. Choosing a particular SRS system is often based on institutional, financial, and administrative factors.[52]
Conclusions
Stereotactic radiosurgery has emerged as a noninvasive and effective means of improving patient survival as well as local control in patients with brain metastases. Two evidence-based management strategies that can be justified on the basis of randomized clinical trials are resection followed by WBRT or WBRT followed by SRS. Stereotactic radiosurgery and resection are overlapping and complementary techniques. Single, large, and superficial lesions in noneloquent brain regions in patients with favorable prognostic factors should be resected. Multiple deep lesions in the medically frail patient should be treated with SRS. Between these two extremes lie the majority of patients, and thus the art of medical management requires an understanding of the strengths and weaknesses of the three tools in the armamentarium: WBRT, SRS, and resection.
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