Topic of the month.... The role of gamma knife in the management of brain metastasis

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Topic of the month.... The role of gamma knife in the management of brain metastasis
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Topic of the month.... The role of gamma knife in the management of brain metastasis

  1. 1. INDEX www.yassermetwally.com INTRODUCTION  INTRODUCTION 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 stereotactic radiosurgery. The authors review the evolution of the techniques used and the indications for stereotactic radiosurgery 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 whole- brain radiotherapy for better regional control. 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 whole-brain radiotherapy improves survival to 3 to 6 months.[6,27] Aggressive local treatments such as resection and radiosurgery in
  2. 2. combination with whole-brain radiotherapy can achieve median survival times of 9 to 12 months in some patients.[2,40] The Radiation Therapy Oncology Group 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 Radiation Therapy Oncology Group 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 ) Table 1. Determination of RPA Class Based on KPS Score, Age, and Extracranial Disease Status* KPS Score Age (yrs) Primary Disease Control RPA Class Survival (mos) 70–100 <50 good 1 7.1 70–100 65 bad 2 4.2 <70> irrelevant irrelevant 3 2.3 * The RPA class is correlated with mean survival. Based on data from Gaspar et al., 1997.. Although RPA class is the most important predictor of survival, aggressive local therapy (such as resection) for metastatic foci in addition to regional therapy (whole-brain radiotherapy) 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 whole-brain radiotherapy compared with 15 weeks in patients who underwent whole- brain radiotherapy 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 stereotactic radiosurgery to control single and multiple brain metastases. In a relatively short time, stereotactic radiosurgery 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 stereotactic radiosurgery comes from Radiation Therapy Oncology Group 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 stereotactic radiosurgery and whole-brain radiotherapy and those in the other group underwent whole-brain radiotherapy alone. Study inclusion criteria were the presence of one to three brain metastases,
  3. 3. 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 stereotactic radiosurgery group did not actually undergo stereotactic radiosurgery, and 28 of 167 patients in the whole-brain radiotherapy arm received salvage stereotactic radiosurgery. Hence, a quot;per protocolquot; analysis probably would have demonstrated an even greater survival advantage for the same groups. On the basis of this randomized trial, stereotactic radiosurgery 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 whole-brain radiotherapy alone or whole-brain radiotherapy and stereotactic radiosurgery. The study was stopped after 60% accrual because the interim analysis showed a dramatic advantage to adding stereotactic radiosurgery.[24] Median time to local failure was 6 months in patients who received whole-brain radiotherapy alone and 36 months in patients who received both whole-brain radiotherapy and stereotactic radiosurgery. Because the study was stopped early, the survival difference between the two groups was not statistically significant. Nevertheless, the authors demonstrated that stereotactic radiosurgery improves local control. Stereotactic Radiosurgery Technique  Stereotactic radiosurgery is performed with either a linear accelerator 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 stereotactic radiosurgery 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 stereotactic radiosurgery 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.
  4. 4. 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 Radiation Therapy Oncology Group outlined maximum tolerated doses in patients undergoing stereotactic radiosurgery after whole-brain radiotherapy 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. Table 2. Final Recommendation of the RTOG Protocol 90-05 Study for Recurrent Metastases* Tumor Size (cm) Recommended Dose (Gy) 1-Year Local Control Rate (95% CI) <2 24 85 (78–92) 2–3 18 49 (30–68) 3–4 15 45 (23–67) * Tumor size is based on the maximum measured tumor diameter in cm. Dose is delivered to the 50% isodose line. Based on data from Shaw et al. and Vogelbaum and Suh. CI = confidence interval. 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 stereotactic radiosurgery 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
  5. 5. established dosing schedule outlined by Radiation Therapy Oncology Group 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 stereotactic radiosurgery 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 stereotactic radiosurgery. 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 stereotactic radiosurgery  Traditional concepts of radioresistance and radiosensitivity to fractionated external beam radiation may not correlate with the response of brain metastasis to stereotactic radiosurgery. For example, brain metastases from melanomas and sarcomas have traditionally been considered radioresistant based on their response to whole-brain radiotherapy (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 stereotactic radiosurgery than those with radiosensitive types. In a multiinstitutional review, patients with melanomas, breast cancer, and renal cell carcinomas treated with stereotactic radiosurgery 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 quot;radioresistantquot; types as the quot;radiosensitivequot; types.[7] The deviation of stereotactic radiosurgery 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 stereotactic radiosurgery can provide local control for tumors that are resistant to standard radiation therapy. Complications of stereotactic radiosurgery  Reported complications of stereotactic radiosurgery 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 stereotactic radiosurgery. 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 stereotactic radiosurgery 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
  6. 6. (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 stereotactic radiosurgery. Meningiomas have been documented to grow in arteriovenous malformation treatment beds.[47] Malignant progression of benign lesions treated with stereotactic radiosurgery is another problem, although deciphering treatment effect from natural history can be difficult.[25] Although radiation-induced neoplasia must be considered when recommending stereotactic radiosurgery 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 stereotactic radiosurgery treatment of metastatic melanoma. The authors reiterate the very low incidence of radiation-induced neoplasia after stereotactic radiosurgery.[28] Craniotomy Compared with stereotactic radiosurgery  Comparative Efficacy  Resection of a single accessible brain metastasis in addition to whole-brain radiotherapy has been the standard of care for single metastases in patients with other favorable prognostic factors. However, stereotactic radiosurgery 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 stereotactic radiosurgery may supplant craniotomy as the new gold standard.[17] One obvious disadvantage to stereotactic radiosurgery 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 stereotactic radiosurgery to craniotomy. Bindal et al.[5] studied 31 retrospectively matched patients treated with stereotactic radiosurgery and 62 patients treated with craniotomy. These authors found a median survival period of 7.5 months in the stereotactic radiosurgery 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 whole-brain radiotherapy compared with those who underwent stereotactic radiosurgery 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 stereotactic radiosurgery. Their rate of local failure for surgery was unusually high at 58%. None of the stereotactic radiosurgery 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
  7. 7. stereotactic radiosurgery 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 stereotactic radiosurgery and whole-brain radiotherapy; patients with more than three tumors and a KPS score less than 70 should undergo whole-brain radiotherapy only. Boyd and colleagues[7] studied 21 reports of stereotactic radiosurgery 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 stereotactic radiosurgery: 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 stereotactic radiosurgery 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 stereotactic radiosurgery  Most studies demonstrate that stereotactic radiosurgery 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 stereotactic radiosurgery, and 454 received whole-brain radiotherapy alone. The authors found that surgery and stereotactic radiosurgery were similarly effective and superior to the use of whole-brain radiotherapy alone. The net cost of surgery was 1.8-fold higher. The average cost per week of survival was $310 for whole-brain radiotherapy, $524 for surgery and whole-brain radiotherapy, and $270 for stereotactic radiosurgery and whole-brain radiotherapy. Rutigliano et al.[42] reviewed the literature on the economic efficiency of stereotactic radiosurgery or surgery with whole-brain radiotherapy from 1974 to 1994 and had similar (although less dramatic) findings, stating the cost as $24,811/life year ($477/week) for stereotactic radiosurgery combined with whole-brain radiotherapy 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 stereotactic radiosurgery. The stereotactic radiosurgery costs were determined by the global operating costs for the gamma knife surgery 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 stereotactic radiosurgery.[56] Compared with conventional craniotomy, stereotactic radiosurgery is a cost-effective treatment for brain metastasis. The decision to pursue craniotomy or stereotactic radiosurgery as a treatment in a particular patient should not be determined by economics. However, because cost, access, and
  8. 8. resource management are increasingly important, these factors must be included in professional discussions of treatment algorithms. Is whole-brain radiotherapy Needed After stereotactic radiosurgery?  Whole brain radiation therapy is an accepted treatment modality for brain metastases. As mentioned, the addition of whole-brain radiotherapy 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 Radiation Therapy Oncology Group 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 whole-brain radiotherapy. This complication occurs 6 to 12 months after irradiation and can be very debilitating.[4,14] This raises the question whether whole-brain radiotherapy 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 whole-brain radiotherapy. Aoyama and colleagues[3] recently published a randomized controlled trial of 132 patients with up to four metastases each who underwent stereotactic radiosurgery or stereotactic radiosurgery followed by whole-brain radiotherapy. 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 stereotactic radiosurgery alone does not provide as good local or distant control as stereotactic radiosurgery with whole- brain radiotherapy. The elimination of whole-brain radiotherapy 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 whole-brain radiotherapy. This study also failed to demonstrate a survival advantage with the addition of whole-brain radiotherapy. 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 whole-brain radiotherapy if patients are treated with stereotactic radiosurgery initially or even with resection. The major reason for withholding whole-brain radiotherapy 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 stereotactic radiosurgery-only treatment plan would reduce the incidence of radiation-induced dementia. An alternative strategy for treatment of new brain metastases is stereotactic radiosurgery alone initially and whole-brain radiotherapy given only to those with treatment failure. Sneed et al.[50] concluded that patients with single metastasis are most likely to benefit from whole-brain radiotherapy. However, they noted that stereotactic radiosurgery without whole-brain radiotherapy led to salvage (delayed) whole-brain radiotherapy 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 stereotactic radiosurgery without whole-brain radiotherapy 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 whole-brain radiotherapy be reserved for cases of numerous metastases or used in a delayed
  9. 9. fashion for recurrence. Conversely, Aoyama et al.[3] found a significantly higher need for salvage whole-brain radiotherapy in patients who had undergone stereotactic radiosurgery alone compared with those treated with stereotactic radiosurgery and whole-brain radiotherapy initially. Further evaluation is needed to clarify the proper use and timing of whole-brain radiotherapy in patients treated with stereotactic radiosurgery. The North Central Cancer Treatment Group Is currently treating patients harboring one to three brain metastases with stereotactic radiosurgery alone and with stereotactic radiosurgery followed by whole-brain radiotherapy. 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 stereotactic radiosurgery System is Best?  There are two fundamental types of stereotactic radiosurgery 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 quot;shotsquot; to the tumor. It relies on the stereotactic Leksell G frame for rigid skull fixation and accurate dose delivery. The nomenclature quot;stereotactic radiosurgeryquot; 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 gamma knife surgery remain the standards by which intracranial stereotactic radiosurgery is defined. The second type of radiosurgical system is based on linear accelerators, or linear accelerators, 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 linear accelerator 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 gamma knife surgery.[43,46] Modern linear accelerators 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 gamma knife surgery and linear accelerator stereotactic radiosurgery. 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 gamma knife surgery. Depending on the situation, this may serve as either an advantage or disadvantage. Choosing a particular stereotactic radiosurgery 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 whole-brain radiotherapy or whole-brain radiotherapy followed by stereotactic radiosurgery. 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 stereotactic radiosurgery. 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
  10. 10. three tools in the armamentarium: whole-brain radiotherapy, stereotactic radiosurgery, and resection. Abbreviation Notes  GKS = gamma knife surgery; KPS = Karnofsky Performance Scale; LINAC = linear accelerator; MR = magnetic resonance; RPA = recursive partitioning analysis; RTOG = Radiation Therapy Oncology Group; SRS = stereotactic radiosurgery; WBRT = whole-brain radiotherapy. References 1. Alexander E III, Loeffler JS: The case for radiosurgery. Clin Neurosurg 45: 32-40, 1999 2. Andrews DW, Scott CB, Sperduto PW, Flanders AE, Gaspar LE, Schell MC, et al: Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet 363: 1665-1672, 2004 3. Aoyama H, Shirato H, Tago M, Nakagawa K, Toyoda T, Ha tano K, et al: Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA 295: 2483-2491, 2006 4. Asai A, Matsutani M, Kohno T, Nakamura O, Tanaka H, Fuji maki T, et al: Subacute brain atrophy after radiation therapy for malignant brain tumor. Cancer 63: 1962-1974, 1989 5. Bindal AK, Bindal RK, Hess KR, Shiu A, Hassenbusch SJ, Shi WM, et al: Surgery versus radiosurgery in the treatment of brain metastasis. J Neurosurg 84: 748-754, 1996 6. Borgelt B, Gelber R, Kramer S, Brady LW, Chang CH, Davis LW, et al: The palliation of brain metastases: final results of the first two studies by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 6: 1-9, 1980 7. Boyd TS, Mehta MP: Stereotactic radiosurgery for brain metastases. Oncology (Williston Park) 13: 1397-1410, 1413, 1999 8. Cairncross JG, Kim JH, Posner JB: Radiation therapy for brain metastases. Ann Neurol 7: 529-541, 1980 9. Chang EL, Hassenbusch SJ III, Shiu AS, Lang FF, Allen PK, Sawaya R, et al: The role of tumor size in the radiosurgical management of patients with ambiguous brain metastases. Neurosurgery 53: 272-281, 2003 10. Chang EL, Selek U, Hassenbusch SJ III, Maor MH, Allen PK, Mahajan A, et al: Outcome variation among quot;radioresistantquot; brain metastases treated with stereotactic radiosurgery. Neurosurgery 56: 936-945, 2005 11. Chernov M, Hayashi M, Izawa M, Ochiai T, Usukura M, Abe K, et al: Differentiation of the radiation-induced necrosis and tumor recurrence after gamma knife radiosurgery for brain metastases: importance of multi-voxel proton MRS. Minim Invasive Neurosurg 48: 228-234, 2005 12. Coia LR, Hanks GE, Martz K, Steinfeld A, Diamond JJ, Kramer S: Practice patterns of
  11. 11. palliative care for the United States 1984-1985. Int J Radiat Oncol Biol Phys 14: 1261-1269, 1988 13. Dare AO, Sawaya R: Part II: surgery versus radiosurgery for brain metastasis: surgical advantages and radiosurgical myths. Clin Neurosurg 51: 255-263, 2004 14. DeAngelis LM, Delattre JY, Posner JB: Radiation-induced dementia in patients cured of brain metastases. Neurology 39: 789-796, 1989 15. Deinsberger R, Tidstrand J: LINAC radiosurgery as single treatment in cerebral metastases. J Neurooncol 76: 77-83, 2006 16. Epstein BE, Scott CB, Sause WT, Rotman M, Sneed PK, Janjan NA, et al: Improved survival duration in patients with unresected solitary brain metastasis using accelerated hyperfractionated radiation therapy at total doses of 54.4 gray and greater. Results of Radiation Therapy Oncology Group 85-28. Cancer 71: 1362-1367, 1993 17. Flickinger JC, Kondziolka D: Radiosurgery instead of resection for solitary brain metastasis: the gold standard redefined. Int J Radiat Oncol Biol Phys 35: 185-186, 1996 18. Flickinger JC, Kondziolka D, Lunsford LD, Coffey RJ, Good man ML, Shaw EG, et al: A multi-institutional experience with stereotactic radiosurgery for solitary brain metastasis. Int J Radiat Oncol Biol Phys 28: 797-802, 1994 19. Flickinger JC, Kondziolka D, Lunsford LD, Kassam A, Phuong LK, Liscak R, et al: Development of a model to predict permanent symptomatic postradiosurgery injury for arteriovenous malformation patients. Arteriovenous Malformation Radio surgery Study Group. Int J Radiat Oncol Biol Phys 46: 1143-1148, 2000 20. Fuller BG, Kaplan ID, Adler J, Cox RS, Bagshaw MA: Ste reotaxic radiosurgery for brain metastases: the importance of adjuvant whole brain irradiation. Int J Radiat Oncol Biol Phys 23: 413-418, 1992 21. Gaspar L, Scott C, Rotman M, Asbell S, Phillips T, Wasserman T, et al: Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 37: 745-751, 1997 22. Kihlstrom L, Karlsson B, Lindquist C: Gamma Knife surgery for cerebral metastases. Implications for survival based on 16 years experience. Stereotact Funct Neurosurg 61 (1 Suppl): 45-50, 1993 23. Kocher M, Treuer H, Voges J, Hoevels M, Sturm V, Muller RP: Computer simulation of cytotoxic and vascular effects of radiosurgery in solid and necrotic brain metastases. Radiother Oncol 54: 149-156, 2000 24. Kondziolka D, Patel A, Lunsford LD, Kassam A, Flickinger JC: Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases. Int J Radiat Oncol Biol Phys 45: 427-434, 1999 25. Kubo O, Chernov M, Izawa M, Hayashi M, Muragaki Y, Mar uyama T, et al: Malignant progression of benign brain tumors after gamma knife radiosurgery: is it really caused by irradiation? Minim Invasive Neurosurg 48: 334-339, 2005 26. Lutterbach J, Cyron D, Henne K, Ostertag CB: Radiosurgery followed by planned
  12. 12. observation in patients with one to three brain metastases. Neurosurgery 52: 1066-1074, 2003 27. Markesbery WR, Brooks WH, Gupta GD, Young AB: Treatment for patients with cerebral metastases. Arch Neurol 35: 754-756, 1978 28. McIver JI, Pollock BE: Radiation-induced tumor after stereotactic radiosurgery and whole brain radiotherapy: case report and literature review. J Neurooncol 66: 301-305, 2004 29. Mehta M, Noyes W, Craig B, Lamond J, Auchter R, French M, et al: A cost-effectiveness and cost-utility analysis of radiosurgery vs. resection for single-brain metastases. Int J Radiat Oncol Biol Phys 39: 445-454, 1997 30. Mehta MP, Rozental JM, Levin AB, Mackie TR, Kubsad SS, Gehring MA, et al: Defining the role of radiosurgery in the management of brain metastases. Int J Radiat Oncol Biol Phys 24: 619-625, 1992 31. Mintz AH, Kestle J, Rathbone MP, Gaspar L, Hugenholtz H, Fisher B, et al: A randomized trial to assess the efficacy of surgery in addition to radiotherapy in patients with a single cerebral metastasis. Cancer 78: 1470-1476, 1996 32. Muacevic A, Kreth FW, Horstmann GA, Schmid-Elsaesser R, Wowra B, Steiger HJ, et al: Surgery and radiotherapy compared with gamma knife radiosurgery in the treatment of solitary cerebral metastases of small diameter. J Neurosurg 91: 35-43, 1999 33. Murray KJ, Scott C, Greenberg HM, Emami B, Seider M, Vora NL, et al: A randomized phase III study of accelerated hyperfractionation versus standard in patients with unresected brain metastases: a report of the Radiation Therapy Oncology Group (RTOG) 9104. Int J Radiat Oncol Biol Phys 39: 571-574, 1997 34. Niranjan A, Gobbel GT, Kondziolka D, Flickinger JC, Lunsford LD: Experimental radiobiological investigations into radiosurgery: present understanding and future directions. Neurosurgery 55: 495-505, 2004 35. Noordijk EM, Vecht CJ, Haaxma-Reiche H, Padberg GW, Voormolen JH, Hoekstra FH, et al: The choice of treatment of single brain metastasis should be based on extracranial tumor activity and age. Int J Radiat Oncol Biol Phys 29: 711-717, 1994 36. O'Neill BP, Iturria NJ, Link MJ, Pollock BE, Ballman KV, O'Fallon JR: A comparison of surgical resection and stereotactic radiosurgery in the treatment of solitary brain metastases. Int J Radiat Oncol Biol Phys 55: 1169-1176, 2003 37. Oh BC, Pagnini PG, Wang MY, Liu CY, Kim PE, Yu C, et al: Stereotactic radiosurgery: adjacent tissue injury and response after high-dose single fraction radiation: part I—- histology, imaging, and molecular events. Neurosurgery 60: 31-45, 2007 38. Paek SH, Audu PB, Sperling MR, Cho J, Andrews DW: Reevaluation of surgery for the treatment of brain metastases: review of 208 patients with single or multiple brain metastases treated at one institution with modern neurosurgical techniques. Neurosurgery 56: 1021- 1034, 2005 39. Patchell RA, Tibbs PA, Regine W, Dempsey RJ, Mohiuddin M, Kryscio RJ, et al: Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. JAMA 280: 1485-1489, 1998.
  13. 13. 40. Patchell RA, Tibbs PA, Walsh JW, Dempsey RJ, Maruyama Y, Kryscio RJ, et al: A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 322: 494-500, 1990 41. Posner JB, Chernik NL: Intracranial metastases from systemic cancer. Adv Neurol 19: 579- 592, 1978 42. Rutigliano MJ, Lunsford LD, Kondziolka D, Strauss MJ, Khan na V, Green M: The cost effectiveness of stereotactic radiosurgery versus surgical resection in the treatment of solitary metastatic brain tumors. Neurosurgery 37: 445-455, 1995 43. Sanghavi SN, Miranpuri SS, Chappell R, Buatti JM, Sneed PK, Suh JH, et al: Radiosurgery for patients with brain metastases: a multi-institutional analysis, stratified by the RTOG recursive partitioning analysis method. Int J Radiat Oncol Biol Phys 51: 426-434, 2001 44. Sawaya R, Ligon BL, Bindal RK: Management of metastatic brain tumors. Ann Surg Oncol 1: 169-178, 1994 45. Selek U, Chang EL, Hassenbusch SJ III, Shiu AS, Lang FF, Allen P, et al: Stereotactic radiosurgical treatment in 103 patients for 153 cerebral melanoma metastases. Int J Radiat Oncol Biol Phys 59: 1097-1106, 2004 46. Shaw E, Scott C, Souhami L, Dinapoli R, Kline R, Loeffler J, et al: Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: final report of RTOG protocol 90-05. Int J Radiat Oncol Biol Phys 47: 291-298, 2000 47. Sheehan J, Yen CP, Steiner L: Gamma knife surgery-induced meningioma. Report of two cases and review of the literature. J Neurosurg 105: 325-329, 2006 48. Shirato H, Takamura A, Tomita M, Suzuki K, Nishioka T, Isu T, et al: Stereotactic irradiation without whole-brain irradiation for single brain metastasis. Int J Radiat Oncol Biol Phys 37: 385-391, 1997 49. Shu HKG, Sneed PK, Shiau CY, McDermott MW, Lamborn KR, Park E, et al: Factors influencing survival after gamma knife radiosurgery for patients with single and multiple brain metastases. Cancer J Sci Am 2: 335-242, 1996 50. Sneed PK, Lamborn KR, Forstner JM, McDermott MW, Chang S, Park E, et al: Radiosurgery for brain metastases: is whole brain radiotherapy necessary? Int J Radiat Oncol Biol Phys 43: 549-558, 1999 51. Sperduto PW: A review of stereotactic radiosurgery in the management of brain metastases. Tech Cancer Res Treat 2: 105-110, 2003 52. Stieber VW, Bourland JD, Tome WA, Mehta MP: Gentlemen (and ladies), choose your weapons: Gamma knife vs. linear accelerator radiosurgery. Technol Cancer Res Treat 2: 79- 86, 2003 53. Sze G, Johnson C, Kawamura Y, Goldberg SN, Lange R, Friedland RJ, et al: Comparison of single- and triple-dose contrast material in the MR screening of brain metastases. AJNR Am J Neuroradiol 19: 821-828, 1998 54. Thng CH, Tay KH, Chan LL, Lim EH, Khoo BK, Huin EL, et al: Magnetic resonance imaging of brain metastases: magnetisation transfer or triple dose gadolinium? Ann Acad
  14. 14. Med Singapore 28: 529-533, 1999 55. Vogelbaum MA, Suh JH: Resectable brain metastases. J Clin Oncol 24: 1289-1294, 2006 56. Wellis G, Nagel R, Vollmar C, Steiger HJ: Direct costs of mi crosurgical management of radiosurgically amenable intra cranial pathology in Germany: an analysis of meningiomas, acoustic neuromas, metastases and arteriovenous malformations of less than 3 cm in diameter. Acta Neurochir (Wien) 145: 249-255, 2003 Addendum  A  new  version  of  topic  of  the  month  publication  is  uploaded  in  my  web  site  every  month  (it   remains for a month and is changed with the monthly update of the neurology bulletin at:.http://neurology.yassermetwally.com) To download the current version of topic of the month publication follow the link  quot;http://neurology.yassermetwally.com/topic.zipquot; You can also download the current version of topic of the month publication from within the  publication or go to my web site at: quot;http://yassermetwally.comquot; to download it. At the end of each year, all the publications are compiled on a single CD-ROM, please author to  know more details. Screen resolution is better set at 1024*768 pixel screen area for optimum display  For an archive of the previously published topics in downloadable PDF format go to  http://yassermetwally.net, then under pages in the right panel, scroll down and click on the text entry quot;topic of the monthquot; In order to view a list of the previously published topics in downloadable PDF format, follow the  link: http://wordpress.com/tag/neurological-topic-of-the-month/ The author: Professor Yasser Metwally, professor of neurology, Ain Shams university, Cairo, Egypt www.yassermetwally.com

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