Journal of Clinical Neuroscience 21 (2014) 731–734

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Review

Stereotactic radiosurgery for brain and spine metastases Patrick J. Bowden a,b, Andrew W. See a,b, Michael J. Dally a,c, Richard G. Bittar a,b,d,e,⇑ a

Epworth Healthcare, Melbourne, VIC, Australia Brain and Spine Tumour Clinic, Melbourne, VIC, Australia c Monash University, Clayton, Melbourne, VIC, Australia d Department of Neurosurgery, Royal Melbourne Hospital, Grattan Street, Parkville, Melbourne, VIC, Australia e Faculty of Health, Deakin University, Burwood, Melbourne, VIC, Australia b

a r t i c l e

i n f o

Article history: Received 24 March 2013 Accepted 20 July 2013

Keywords: Brain Metastasis Radiosurgery Radiotherapy Spine Stereotactic radiosurgery Tumour

a b s t r a c t Metastases to the brain and spine are common and difficult to treat. Stereotactic radiosurgery (SRS) is a non-invasive treatment option for some individuals, and may obviate the need for open surgery and/or whole brain radiotherapy. Over the past decade there has been an increased number of patients undergoing SRS for the treatment of metastatic disease, and multiple published studies show favourable results in terms of local disease control. We review the available literature pertaining to the application of SRS for the treatment of brain and spine metastases, together with its limitations and outcomes. Ó 2013 Elsevier Ltd. All rights reserved.

1. Introduction Metastases to the brain and spine are common and difficult to treat. The exact incidence of metastatic brain and spine tumours is unknown, however it is estimated that around 25% of individuals with cancer will develop intracranial metastases [1], and 30–90% will develop spinal metastases [2]. Furthermore, as systemic therapies improve the survival of cancer patients, the durability and effectiveness of local treatment of spine and brain metastases must assume greater importance in terms of quality of life and symptom control. Until recent years, the mainstay of treatment of such metastases comprised surgery, conventional radiotherapy and chemotherapy. The emergence of stereotactic radiosurgery (SRS), together with advances in its delivery, has resulted in a paradigm shift in the way that metastatic disease of the brain and spine is managed. We review the contemporary literature pertaining to the use of SRS in the treatment of these tumours. 2. What is SRS? SRS represents one of the most significant technical improvements in radiotherapy delivery since the introduction of the linear ⇑ Corresponding author. Address: PO Box 3096, Cotham LPO, Kew, VIC 3101, Australia. Tel.: +61 3 8862 0000; fax: +61 3 9816 8564. E-mail address: [email protected] (R.G. Bittar). 0967-5868/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jocn.2013.07.043

accelerator in the 1960s. While conventional radiation has become more conformal with advances in the three dimensional (3D) input of planning information, not all so-called ‘‘3D conformal radiation’’ is SRS [3]. SRS intentionally delivers ultra-high ‘‘ablative’’ radiation doses to small intracranial or spinal targets, well in excess of what can be achieved with conventional methods. Despite the fact that these radiation doses commonly exceed normal tissue tolerance, the morbidity of SRS therapy is kept to an extremely low level largely due to the fact that stereotactic systems are able to define, conform to, verify and track targets with sub-millimetre accuracy [4] leaving little and in some cases no disruption to surrounding healthy tissue. In addition to improved imaging and dosimetry, which describe how the radiation interacts with different tissue densities such as lung and bone, fiducial tracking is an essential component. Here, external body markers or the patient’s bony anatomy is used to define the position of the target, in the same way that global positioning satellites that surround the earth exactly define our position when stuck in traffic. Robotics can then be used to correct beam alignment with six degrees of freedom (X, Y, Z, yaw, pitch and roll) enabling tight margins and reduced dose to critical normal structures, such as the optic nerves or spinal cord. In addition, SRS courses of therapy are quick, painless and, in the majority of cases, can be delivered in the ambulatory setting. These compelling attributes of SRS have led to a plethora of clinical research initiatives that consistently show better outcomes

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when SRS is used either as an adjunct or in lieu of traditional treatments in select patients with metastatic cancer involving the spine or brain. At present there are several commercially available stereotactic systems, including Novalis Tx (Varian Medical Systems, Palo Alto, CA, USA and Brainlab AG, Heimstetten, Germany), Cyberknife (Accuray Inc, Sunnyvale, CA, USA) and Gamma Knife (Elekta AB, Stockholm, Sweden) with each system offering slightly different clinical capabilities. In Australia, SRS is still considered to be under-utilised, largely attributable to a lack of access. 3. Brain metastases The mainstay of treatment of brain metastases has comprised surgical excision (craniotomy) and/or whole brain radiotherapy (WBRT), with the treatment selected based on a number of factors and individualised to each patient. Surgical excision is an invasive procedure, requiring a period of hospitalisation and carrying significant risks, including haemorrhage, infection, seizures, stroke and mortality. WBRT also carries short-term side effects, including asthenia, alopecia and the potential to impact on neurocognitive function, which is particularly evident in those patients who have prolonged survival [5–7]. Some studies have pointed to improved local control where SRS and WBRT have been used together, but in some situations, such as high performing patients with controlled systemic disease and one to three brain metastases, WBRT can be delayed without detriment [8]. Kocher et al. demonstrated no significant difference in overall survival in those who received WBRT after SRS when compared to those who did not receive WBRT, with no significant difference in the duration of functional independence between the two groups [8]. The concept of using a non-invasive approach, such as SRS, which can defer or eliminate the need for surgery and WBRT, is therefore appealing. SRS is being increasingly used to treat many patients with metastatic brain tumours. Open surgery remains the preferred option for large (generally more than 3.5 cm) tumours causing significant symptoms or with marked surrounding oedema. SRS is particularly useful for small or deep tumours, and for multiple lesions. 4. Is SRS as efficacious as open surgery? Rades et al. found that SRS alone was as effective as conventional surgery plus WBRT in patients with one or two metastatic brain tumours [9]. In a subsequent study, the same authors compared SRS plus WBRT with conventional operation plus WBRT in patients with one to three metastatic brain tumours. One year overall survival was 56% in the SRS group versus 47% in the surgery group (p = 0.034), and 1 year local control rates were 82% in the SRS group (compared with 66% in the surgery group; p = 0.006). They concluded that, in terms of overall survival and reduced local recurrence, SRS was at least as effective as surgery [10]. Aoyama et al. undertook a randomised study of SRS versus SRS plus WBRT. While an increased control rate was found in the combined arm (recurrence rate 46% versus 76%), no significant reduction in neurological deaths or survival benefit was noted [11]. Roos et al. undertook a similar randomised, controlled study in Australia examining differences in outcome between surgery plus WBRT versus SRS plus WBRT [12]. The study closed prematurely, due to slow enrolment, however the results failed to demonstrate a significant difference between the two groups in terms of local recurrence or overall survival. SRS may be particularly useful in the treatment of renal cell carcinoma and melanoma metastases, two tumour types traditionally thought of as radioresistant. Lwu et al. used SRS alone to treat metastatic melanoma and renal cell carcinoma, without surgery or

additional WBRT [13]. They found 12 month local control rates of 75% for melanoma, and 91% for renal cell carcinoma. Jahanshahi et al. demonstrated the more favourable response of melanoma to larger doses of radiation, and achieved an 84% 12 month local control rate for intracranial metastases [14]. The magnitude of these local control rates is similar to those reported following surgical resection [15]. Hanson et al. reviewed the literature on the use of SRS for the treatment of radioresistant melanoma and renal cell carcinoma brain metastases, and found this modality to be both safe and effective [16]. Brainstem metastases are extremely difficult to treat surgically, due to their deep and critical location, and therefore the extremely high risk of major neurological morbidity and mortality with an open operation. SRS has been shown to produce a good 1 year local control rate (88%) and a low complication rate (70 years) Spine

SRS

102

11

91% renal cell carcinoma 75% melanoma 90%

SRS

149

16

81%

Grade 3 and 4 7%, neurological 13% (seizures, motor and speech deficits, confusion) Grade 3 8%

Spine

SRS

61

20

88% (18 months)

Neurological deterioration 3%

Spine

SRS

500

21

88% (21 months)

Nil reported

CTCAE = Common Terminology Criteria for Adverse Events, SRS = stereotactic radiosurgery, WBRT = whole brain radiotherapy.

including fatigue and physical functioning at 8 weeks, global health at 9 months, and cognitive functioning at 12 months [23]. It is now the practice of many specialist centres (including ours) to delay or avoid WBRT following SRS where possible, and to treat most recurrences with either SRS or surgery. 7. SRS as an adjunct to surgery Local tumour recurrence following surgical resection of metastases may be problematic, and WBRT has been used in an attempt to reduce its likelihood, as well as the risk of distant intracranial tumour formation. Leptomeningeal tumour spread and direct invasion into the surrounding brain may be the biological basis for tumour recurrence, and adjuvant treatment of the peritumoural region aims to eradicate residual cancer cells. SRS as an adjunct to surgery was used by Robbins et al. who found an overall recurrence rate of 81%, a median survival time of 12.1 months, and the requirement for salvage WBRT in only 35% of patients [24]. Jensen et al. treated 112 surgical resection cavities with tumour bed SRS (without adjuvant WBRT) and achieved an 80% local tumour control rate at 1 year [25]. Their median overall survival was 10.9 months, and 46% required salvage WBRT at 1 year. More recently, Minniti et al. utilised multidose SRS (three treatments of 9 Gy) to treat the resection cavities following the resection of large (>3 cm) brain metastases in 101 patients with a single metastasis [26]. They demonstrated a 2 year survival rate of 34%, with a 1 year local control rate of 93% (this decreased to 84% at 2 years). Importantly, they found similar local control rates for radioresistant (renal cell carcinoma, melanoma) and radiosensitive (breast, non-small cell lung cancer) tumours. Their rate of symptomatic radionecrosis was 5% (4% had asymptomatic radionecrosis). 8. Spine metastases The traditional management of spine metastases involved consideration of conventional low dose palliative radiation therapy. This is generally undertaken with a single posterior megavoltage beam which delivers a greater dose to the spinal cord than the

(usually) anterior tumour in the vertebral body. Although pain reduction is seen in 60% of people with this approach, complete pain eradication is achieved in relatively few (around a quarter of patients) [27] with the majority of people experiencing recrudescent symptoms beyond 3 months. Furthermore, conventional radiation therapy shrinks tumours slowly, which may expose the patient to more functional compromise when spinal cord compression is evident or imminent. Outcomes may be poorer when dealing with radioresistant histologies (renal cell carcinoma, malignant melanoma or sarcoma) or in the presence of spinal instability. The management of spinal metastases has evolved significantly following the publication of a randomised controlled trial by Patchell in 2005 [28]. This seminal study demonstrated a clear benefit of decompressive surgery followed by fractionated radiotherapy over fractionated radiotherapy alone. Klimo et al. conducted a meta-analysis of surgery versus conventional radiotherapy, and their results fell similarly in favour of operative treatment [29]. Surgical intervention has since been frequently advocated in order to regain or maintain mobility, and reduce the need for opioid analgesic medications. The use of SRS to treat spinal metastases has also become relatively widespread internationally over the past decade, with detailed inclusion and exclusion criteria recently published [30]. The goals of this treatment are generally to treat malignant spinal pain, minimise the chance of spinal cord compression, and improve quality of life. In many cases SRS may be used alone, thereby avoiding the need for more invasive procedures [31]. In other cases it is used in conjunction with surgical decompression, stabilisation or vertebroplasty [30,32]. The development of improved SRS approaches, such as intensity modulated radiotherapy or Hybrid Arc (Brainlab–AG) have allowed the more precise delivery of high dose radiotherapy to metastatic spinal tumours whilst avoiding significant exposure of the spinal cord to radiation. Gerzsten et al. retrospectively studied the outcomes of 500 patients treated with spinal SRS [31]. They showed a long-term pain control rate of 86%, and a tumour control rate of approximately 90%. Breast and lung metastases had 100% long-term local control rates, with renal cell carcinoma and melanoma having 87% and 75% long term control rates respectively. Garg et al. studied patients prospectively, and achieved an 18 month local control rate of

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88%, and freedom from neurological deterioration rate of 82% [33]. A recent review by Hall et al. revealed a cumulative local control rate of around 90%, with a risk of radiation-induced myelopathy of less than 1% [34]. The results of these and other studies support the role of SRS as an initial treatment option for well-selected individuals with metastatic spinal disease. The precise targeting of metastatic disease and careful avoidance of the spinal cord or cauda equina may allow retreatment using stereotactic body radiosurgery in carefully selected individuals. This has not previously been possible with conventional radiation, where it is rare to be able to deliver any meaningful dose whilst respecting spinal cord tolerance [35]. The main risk from such an approach is vertebral body collapse. One multivariate analysis suggests that location below T10, more than 40% vertebral involvement and predominately lytic disease are associated with increased risk [36]. A more recent study reported that the risk of vertebral body fracture following SRS was around 20% [37]. Whilst in many cases these can be managed conservatively, in some individuals surgical stabilisation may be required either prophylactically or to treat an unstable fracture. 9. Conclusion SRS of the brain and spine has emerged as an effective, non-invasive outpatient treatment for many individuals with metastatic disease. Advances in technology and experience are providing an opportunity to treat a wider range of pathologies with relative safety. In many cases SRS represents an alternative to open surgery or traditional radiotherapy, however meticulous patient selection is paramount. High quality prospective outcome data, preferably in the form of randomised controlled trials, should answer many questions about the role and efficacy of SRS. Conflicts of interest/disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. References [1] Fox BD, Cheung VJ, Patel AJ, et al. Epidemiology of metastatic brain tumors. Neurosurg Clin N Am 2011;22:1–6. [2] Sciubba DM, Gokaslan ZL. Diagnosis and management of metastatic spine disease. Surg Oncol 2006;15:141–51. [3] Barnett GH, Linskey ME, Adler JR, et al. Stereotactic radiosurgery—an organized neurosurgery-sanctioned definition. J Neurosurg 2007;106:1–5. [4] Ackerly T, Lancaster CM, Geso M, et al. Clinical accuracy of ExacTrac intracranial frameless stereotactic system. Med Phys 2011;38:5040–8. [5] DeAngelis LM, Delattre JY, Posner JB. Radiation-induced dementia in patients cured of brain metastases. Neurology 1989;39:789–96. [6] Asai A, Matsutani M, Kohno T, et al. Subacute brain atrophy after radiation therapy for malignant brain tumor. Cancer 1989;63:1962–74. [7] Frytak S, Shaw JN, O’Neill BP, et al. Leukoencephalopathy in small cell lung cancer patients receiving prophylactic cranial irradiation. Am J Clin Oncol 1989;12:27–33. [8] Kocher M, Soffietti R, Abacioglu U, et al. 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] Rades D, Bohlen G, Pluemer A, et al. Stereotactic radiosurgery alone versus resection plus whole-brain radiotherapy for 1 or 2 brain metastases in recursive partitioning analysis class 1and 2 patients. Cancer 2007;109: 2515–21. [10] Rades D, Kuetera J-D, Veningac T, et al. Whole brain radiotherapy plus stereotactic radiosurgery (WBRT + SRS) versus surgery plus whole brain radiotherapy (OP + WBRT) for 1–3 brain metastases: results of a matched pair analysis. Eur J Cancer 2009;45:400–4. [11] Aoyama H, Shirato H, Tago M, et al. 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.

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