- Department of Radiation Oncology and Neurological Surgery, University of Washington and Seattle Cancer Care Alliance, 1959 NE Pacific Street, Box 356043, Seattle, WA 98195, United States
Jason K. Rockhill
Department of Radiation Oncology and Neurological Surgery, University of Washington and Seattle Cancer Care Alliance, 1959 NE Pacific Street, Box 356043, Seattle, WA 98195, United States
DOI:10.4103/2152-7806.111295Copyright: © 2013 Halasz LM This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
How to cite this article: Halasz LM, Rockhill JK. Stereotactic radiosurgery and stereotactic radiotherapy for brain metastases. Surg Neurol Int 02-May-2013;4:
How to cite this URL: Halasz LM, Rockhill JK. Stereotactic radiosurgery and stereotactic radiotherapy for brain metastases. Surg Neurol Int 02-May-2013;4:. Available from: http://sni.wpengine.com/surgicalint_articles/stereotactic-radiosurgery-and-stereotactic-radiotherapy-for-brain-metastases/
Stereotactic radiosurgery (SRS) and hypofractionated stereotactic radiotherapy (HFSRT) have become important treatment modalities for brain metastases. While effective, there are still areas of extensive debate on its appropriate use in patients with life-limiting diseases. This review provides an overview of the indications and challenges of SRS and HFSRT in the management of brain metastases.
Keywords: Brain metastases, brainlab, cyberknife, gamma knife, hypofractionated, radiosurgery, stereotactic
Brain metastases cause significant morbidity and mortality for patients with cancer. In the past, the median survival of patients with brain metastases without treatment was generally a few months. This was largely due to the presence of significant symptoms and larger lesions at presentation. It was not routine to scan asymptomatic patients. Treatment with whole brain radiation therapy (WBRT) improved survival over best supportive care and was given with palliative intent to improve symptoms temporarily. Response rates for WBRT were 40-50%.[
WHAT IS STEREOTACTIC RADIOSURGERY/STEREOTACTIC RADIOTHERAPY
The key component of SRS and hypofractionated stereotactic radiotherapy (HFSRT) is the precise delivery of a high dose of radiation to a target with rapid dose drop off to the surrounding normal tissues. There are a variety of devices that can be used, including Gamma Knife (Elekta AB, Stockholm, Sweden), Cyberknife (Accuray, Sunnyvale, CA, USA), gantry–based linear accelerator (LINAC) systems (e.g., Novalis TX, BrainLab) and less commonly proton beam-based systems.
Gamma Knife uses a fixed immobilization frame and imaging obtained with the frame in place to create a stereotactic grid “space” for treatment planning. Multiple imaging modalities can be used for treatment planning with all scans co-localized into the same space. The most common modality for treatment of brain metastases is fine cut postcontrast magnetic resonance imaging (MRI). Alternatively, computed tomography (CT) with contrast can be used when patients have contraindications to MRI, such as a defibrillator or pacemaker. Positron emission tomography (PET) scans can also be used to incorporate biological relevant information into the treatment planning process.
Using the latest version of Gamma Knife Perfexion, the delivery of radiation is carried out by 192 different radiation beams or ports all focused on a single isocenter. The size of the isocenter can be varied with a 4, 8, or 16 mm collimator. This effectively creates a dose cloud with the same size. Multiple isocenters or shots can be combined to create custom shapes. The collimators can be mixed and matched or blocked to further customize the dose delivery. During treatment, the patient is immobilized by fixing the head frame to the treatment couch, which precisely positions the patient to the correct coordinates for each isocenter or shot. When the treatment is complete, the patient is removed from the treatment machine and the head frame is removed. Generally the prescription doses for brain metastases vary between 12 and 24 Gy to the 50% isodose line. Thus the middle of the target receives twice that dose (24-48 Gy). Generally these doses are based on findings from the Radiation Therapy Oncology Group (RTOG) 90-05, a dose escalation study undertaken to determine the highest dose with acceptable toxicity based on tumor size.[
Cyberknife utilizes a linear accelerator attached to the end of a robotic arm. Planning is somewhat similar in that CT, MRI, and PET can all be used when co-localized with a treatment planning CT. Since the head frame is not attached to the skull, the scans can be obtained prior to the day of treatment and treatment planning can take place without the patient being present. Treatment planning is achieved by utilizing different sized collimators from thousands of possible beam directions or multiple pencil beams. Doses are generally similar to those used for Gamma Knife but usually are prescribed to the 70-80% isodose line. Cyberknife also allows treatment of larger lesions with multiple treatments (HFSRT) over several days. Patients are treated with an immobilization mask and on-board orthogonal X-rays to assure positioning. The orthogonal imaging is repeated multiple times throughout treatment to assure delivery accuracy.
Gantry-based LINAC systems use either fixed circular collimators or multileaf collimators. As with other systems, treatment planning imaging is based on CT but other images including MRI and PET can be fused to the treatment CT. Once again, on-board imaging is used to assure patient alignment. The treatment can be delivered as either multiple arcs or as one continuous arc. The isocenter is generally in the middle of the target lesions; however, newer systems with Volumetric Modulated Arc Therapy (VMAT) allow for treatment of multiple lesions in a single arc. Doses again are in the 12-24 Gy range for single fraction treatments generally prescribed to the 60-80% isodose line.
There are pluses and minuses to each system. Gamma Knife may have some benefit in treating multiple lesions in terms of shorter treatment times and efficiency. Furthermore the composite brain dose may be less. The down side is the frame-based system, which patients may find uncomfortable, and the need to reload the radiation delivery sources roughly every 5 years. Cyberknife, BrainLab, and LINAC systems can treat solitary lesions the fastest due to the higher radiation output when compared with Gamma Knife. However, most systems are only able to treat one lesion at a time, and multiple lesions take longer. This does not hold true for systems that can use VMAT – an arcing treatment technique where the beam is delivered continuously as the gantry moves around the patient. In addition, LINAC-based systems may be used for anatomic sites other than brain and thus may be more practical for centers with smaller radiosurgery volume.
Proton stereotactic systems are quite rare. Either a frame based or bite block immobilization system can be used. The lesion is generally treated with two to three ports such that the dose drops off rapidly on the distal side of the lesion and the isodose lines can be shaped with compensators. The advantage of protons is that there is no exit dose, decreasing integral dose to the brain.
In general, SRS describes dose delivered in a single treatment, whereas HFSRT is delivered in 2-5 fractions. However, the dose per fraction for HFSRT is generally larger (5-9 Gy) than conventionally fractionated radiation therapy (1.8-2 Gy). Some standard hypofractionated schemes include 18-30 Gy in 3-5 fractions. The limitation to five fractions is likely most prevalent in the US due to reimbursement structure. Stereotactic treatments are not covered after five fractions. There have been no trials that have clearly identified that HFSRT is best performed in 2-5 fractions.
Given the initial prevalence of frame-based immobilization devices (Gamma Knife and some LINAC-based systems), many of the initial studies employed single fraction treatments due to the discomfort of either multiple frame placements or multiple days that patients would wear the frame. Many lesions respond quite well to single fraction treatments particularly smaller lesions. However, larger lesions, generally greater than 3 cm, treated in a single fraction have been associated with increased rates of acute side effects. Furthermore as on-board imaging has become more prevalent, it is easier to administer multiple sessions. There are no randomized trials comparing single fraction treatment with multiple hypofractionated treatments. For larger lesions hypofractionation possibly reduces the risk of toxicity, and there may also be a radiobiological benefit of multiple treatments.
SRS and HFSRT have been increasingly used as treatment for brain metastases for several reasons. For few metastases, advantages compared with neurosurgical resection include its noninvasive approach, suitability for outpatient treatment, ability to treat surgically unresectable areas such as the brainstem, and ability to treat multiple lesions. For multiple metastases, advantages compared with WBRT include improved local control, fewer neurocognitive side effects, and a shorter treatment course. In addition, retrospective series have shown that radioresistant histologies including renal cell carcinoma and melanoma have control rates after SRS that are similar to radiosensitive tumor types.
Initially, SRS was used and tested in clinical trials as a way of improving outcomes for patients with few metastases. Multiple trials showed improved intracranial control with adding SRS to WBRT.[
Therefore, subsequent randomized trials tested SRS alone as a new treatment paradigm. Indeed, multiple randomized trials have shown that withholding WBRT for one to four brain metastases does not compromise overall survival.[
There has never been a head to head trial comparing SRS and surgery. However, retrospective series and results from EORTC 22952 suggest that SRS control rates are not inferior to surgical resection. Results from both of these sources are biased by how patients were assigned to surgery or SRS, and so direct comparison is not possible. In reality, SRS and surgery have different strengths and weaknesses as treatment for patients with brain metastases. Whereas surgery may be the optimal treatment for patients with symptoms due to mass effect, radiosurgery allows us to treat surgically inaccessible lesions. Rapid dose drop off provided by radiosurgery allows us to treat lesions that are adjacent to critical structures and still preserve neurological function. Perhaps, this is most clearly seen in treating brain metastases in the brainstem [
Since no overall survival benefit has been shown in adding WBRT to SRS, attention has shifted from using SRS to improve overall survival to using SRS to improve quality of life and neurocognitive outcomes. The neurocognitive decline associated with WBRT, described many years ago by DeAngelis et al., have become increasingly important as patients with metastatic cancer are living longer with improvements in detection, systemic therapies, and supportive care. Though the median survival of patients with brain metastases remain poor overall, certain subgroups with good prognostic factors have median survival of 15-25 months.[
The EORTC 22952 also assessed quality of life and cognitive function with EORTC QLQ-C30 and BR20 brain cancer specific questionnaires, however, only 45% completed the analysis at one year. Patients who underwent WBRT had lower physical functioning at 8 weeks and cognitive function scores at one year, however, there were no significant differences in global Health Related Quality of Life.[
Though the interpretation of published trials results may be controversial, the use of SRS for brain metastases has been steadily increasing in the US.[
Timing of treatment
In addition to avoiding or delaying WBRT to prevent associated side effects, the one day course of SRS may have quality of life implications. WBRT generally takes 2-3 weeks of daily treatment. For patients with poor prognosis, this may represent a significant percentage of the time they have left. For all patients, this may delay starting systemic treatment since chemotherapy is usually held during WBRT.
CHALLENGES IN RADIOSURGERY
One of the major challenges after SRS is determining whether imaging results and clinical decline represent treatment effect or true tumor progression [
Woman with metastatic breast cancer with multiple brain metastases that had a right frontal resection cavity treated with stereotactic radiosurgery 4 weeks after resection of the lesion. She developed significant radiation necrosis possibly caused by radiation recall after a Vinorelbine infusion. The area of contrast enhancement changed dramatically over a year and a half with the only treatment being steroids (no further radiation or surgery to this lesion). Further resection was not an option due to her overall clinical situation
If treatment effect is suspected, most patients will respond to steroids with improvement in symptoms and can be followed conservatively. However, some patients will become quite symptomatic or intolerant of steroids and require surgical intervention. This treatment decision is often difficult in a patient with progressive systemic disease and/or poor performance status. While surgical resection of an enlarging contrast enhancing lesion may improve neurological symptoms, the recovery required after neurosurgical resection may be difficult for a patient with deteriorating condition. However, increasing doses of steroids often lead to significant side effects including insomnia, anxiety, weight gain, adrenal insufficiency, and hyperglycemia. Bevacizumab, a monoclonal antibody targeting the vascular endothelial growth factor (VEGF) receptor is well known for decreasing contrast enhancement and vasogenic edema in recurrent high-grade gliomas and multiple reports have suggested that bevacizumab may have the same effect on radiation induced necrosis.[
If the clinical picture is consistent with recurrence either within or outside of the radiosurgery target, there are multiple options for salvage treatment. However, deciding the best approach is challenging. One of the most important factors in deciding salvage treatment is the overall clinical picture at the time of recurrence. For an isolated tumor recurrence after prior SRS in a patient with control systemic disease then repeat SRS to the same lesion is possible, however, it carries an increased risk of radionecrosis.[
Size of lesions
The dose escalation RTOG trial 90-05 established that the size of the lesion treated with radiosurgery directly correlates with the risk of side effects due to increased vasogenic edema and radionecrosis [
For larger lesions, many have also taken the approach of HFSRT, which capitalizes on the stereotactic precision of radiosurgical devices but delivers dose over multiple fractions. Many tumors respond quite well to these courses, however, further investigation into the optimal treatment schedules, doses, and their relationship to the size of targets needs to be pursued.
Number of lesions
One of the biggest misconceptions regarding SRS is that it is only helpful for patients with fewer than four lesions [
Sixty-six-year-old male with metastatic renal cell cancer. Thirty-three lesions have been treated over two and one-half years. MRI shows representative images of the same anatomical location over time with the oldest scans on the left and newest on the right. The blue circles represent previously treated lesions and the yellow/green represent lesions most recently treated
Much of the controversy surrounding the efficacy of radiosurgery compared with WBRT is driven by the cost differential between the two treatment approaches. Throughout the US, the radiation therapy costs for patients with brain metastases are increased in those who receive SRS and the more frequent imaging surveillance associated with a SRS alone approach may also add to the overall costs.[
Role of radiosurgery in treating resection cavities
When patient do have metastases resected, there is an approximately 50% chance of a local recurrence within the resection cavity. Previously patients underwent whole brain irradiation, which included the resection cavity to improve local control. There have now been retrospective studies showing improved local control when the resection cavity has been treated with SRS.[
SRS and HFSRT have become increasingly important treatment techniques in the management of brain metastases. An approach of SRS alone as initial treatment of brain metastases has allowed patients to delay or avoid WBRT and its associated side effects. Further studies are necessary to determine which patients may benefit from this approach. One of the most critical questions is how benefit is defined and from who's perspective – patient, provider, payer, or society. Many centers with high volume practices feel comfortable treating multiple lesions at multiple time points in patients with an excellent performance status. However, whether the cost of this approach is justified has yet to be defined.
1. Andrews DW, Scott CB, Sperduto PW, Flanders AE, Gaspar LE, Schell MC. 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. 2004. 363: 1665-72
2. Aoyama H, Shirato H, Tago M, Nakagawa K, Toyoda T, Hatano K. Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA. 2006. 295: 2483-91
3. Bhatnagar AK, Flickinger JC, Kondziolka D, Lunsford LD. Stereotactic radiosurgery for four or more intracranial metastases. Int J Radiat Oncol Biol Phys. 2006. 64: 898-903
4. Chang EL, Wefel JS, Hess KR, Allen PK, Lang FF, Kornguth DG. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: A randomised controlled trial. Lancet Oncol. 2009. 10: 1037-44
5. Essig M, Waschkies M, Wenz F, Debus J, Hentrich HR, Knopp MV. Assessment of brain metastases with dynamic susceptibility-weighted contrast-enhanced MR imaging: Initial results. Radiology. 2003. 228: 193-9
6. Halasz LM, Weeks JC, Neville BA, Taback N, Punglia RS. Use of stereotactic radiosurgery for brain metastases from non-small cell lung cancer in the United States. Int J Radiat Oncol Biol Phys. 2013. 85: e109-16
7. Horky LL, Hsiao EM, Weiss SE, Drappatz J, Gerbaudo VH. Dual phase FDG-PET imaging of brain metastases provides superior assessment of recurrence versus post-treatment necrosis. J Neurooncol. 2011. 103: 137-46
8. Kocher M, Soffietti R, Abacioglu U, Villà S, Fauchon F, Baumert BG. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: Results of the EORTC 22952-26001 study. J Clin Oncol. 2011. 29: 134-41
9. 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. 1999. 45: 427-34
10. Lawrence YR, Li XA, el Naqa I, Hahn CA, Marks LB, Merchant TE. Radiation dose-volume effects in the brain. Int J Radiat Oncol Biol Phys. 2010. 76: S20-7
11. Matuschek C, Bölke E, Nawatny J, Hoffmann TK, Peiper M, Orth K. Bevacizumab as a treatment option for radiation-induced cerebral necrosis. Strahlenther Onkol. 2011. 187: 135-9
12. Mehta MP, Shapiro WR, Glantz MJ, Patchell RA, Weitzner MA, Meyers CA. Lead-in phase to randomized trial of motexafin gadolinium and whole-brain radiation for patients with brain metastases: Centralized assessment of magnetic resonance imaging, neurocognitive, and neurologic end points. J Clin Oncol. 2002. 20: 3445-53
13. Robbins JR, Ryu S, Kalkanis S, Cogan C, Rock J, Movsas BS. Radiosurgery to the surgical cavity as adjuvant therapy for resected brain metastasis. Neurosurgery. 2012. 71: 937-43
14. Shaw E, Scott C, Souhami L, Dinapoli R, Kline R, Loeffler J. 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. 2000. 47: 291-8
15. Soffietti R, Kocher M, Abacioglu UM, Villa S, Fauchon F, Baumert BG. A European Organisation for Research and Treatment of Cancer Phase III Trial of Adjuvant Whole-Brain Radiotherapy Versus Observation in Patients With One to Three Brain Metastases From Solid Tumors After Surgical Resection or Radiosurgery: Quality-of-Life Results. J Clin Oncol. 2013. 31: 65-72
16. Sperduto PW, Chao ST, Sneed PK, Luo X, Suh J, Roberge D. Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: A multi-institutional analysis of 4,259 patients. Int J Radiat Oncol Biol Phys. 2010. 77: 655-61
17. Last accessed on 2010. Available from: http://seer.cancer.gov/index.html .