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Neurosurgical applications of radiotherapy
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radiotherapy (or stereotactic radiotherapy e SRT) is the term used when the radiation is delivered over several, generally daily fractions, in a course of few days (3e5 fractions, hypofractionated radiotherapy) or few weeks (up to 33 fractions, conventionally fractionated radiotherapy).1 In conventional radiotherapy, the dose is fractionated over multiple sessions to spare the normal brain while causing optimal tumour damage and consequent treatment success. Radiation-induced cell damage mainly relies on tumour DNA double-strand damage that results in cell apoptosis (inhibition of cell repair) and reproductive cell block (inhibition of repopulation). More radio resistant tumour cells are those proliferating in absence of oxygen (lack of reoxygenation) or able to redistribute themselves within more radio-resistant phases of the cell cycle (redistribution). These radiobiological pillars e so-called ‘4Rs’ e were initially introduced to provide a means of understanding for the success or failure of fractionated radiotherapy. Later, intrinsic ‘radiosensitivity’ was added as a 5th R to explain, at the mechanistic level, the marked different radio response of different cancerous conditions.2 While explaining the mechanisms through which fractionated radiotherapy acts, the same biological considerations do not describe the effects of high single-dose/hypofractionated treatments. Direct tumour cell death is insufficient after a single high dose of radiation and might only account for the death of the more radiosensitive cells. It has been observed that a single large dose of radiation (>10 Gy) induces severe vascular damages in experimental tumours, causing secondary and additional tumour cell death. This process would consequently trigger the production of a large number of tumour antigens able to initiate an immune mediated response (usually within 1e2 weeks from treatment) that inhibits tumour cells survival and the maintenance of the correct intratumoural microenvironment.3 Although the precise mechanism behind the clinical benefit of RS is still not fully elucidated and remains largely theoretical, these experimental observations would support the responses to RS detected in both malignant, benign or vascular treated lesions.
Neurosurgical applications of radiotherapy Francesca Solda Cornel Tancu Neil Kitchen Naomi Fersht
Abstract The term ‘radiosurgery’ (RS) indicates a high precision localized technique of irradiation used as an alternative to surgical excision in patients with malignant or benign conditions, both in the brain and in the body. Brain RS has been historically identified with ‘stereotactic radiotherapy’. The term refers to the long-established neurosurgical technique of localizing the position of a lesion in the brain by using a system of external 3D co-ordinates coupled with rigid head immobilization device (often fixed to the skull). A high dose of radiation is delivered to the target stereotactically identified and a safe and accurate treatment is achieved, minimizing the dose of radiation to the surrounding brain. While for some techniques the traditional stereotactic localization has been replaced by the integration of modern imaging with non-invasive accurate immobilization, the term ‘stereotactic’ is still maintained in the clinical practice. Over the past 30 years, the implementation of powerful diagnostic imaging devices and of new radiotherapy equipment has contributed to the large diffusion of brain RS. RS plays an important role in the management of brain tumours, vascular and functional brain lesions and the expertise of the multidisciplinary treating team (clinical oncologists, neurosurgeons, neuro-radiologists and medical physics) contributes to the treatment success rate.
Keywords Gamma knife; Linac-based radiosurgery; outcome; radiosurgery; techniques
Biological background of brain radiosurgery
Radiosurgical techniques
Radiosurgery (RS) specifically refers to a radiation treatment given in a single fraction while fractionated high precise
Regardless of the technology and the techniques adopted to deliver it, brain RS aims to: accurately identify the treatment target within the brain precisely calculate the dose to deliver to the treatment target by using a computerized treatment planning system deliver precisely a high dose of radiation in one single or few (3e5) fractions minimize the dose received by the surrounding brain, hence minimizing the risk of normal tissue injury. In general, the treatment target is identified on high-resolution imaging (usually thin cuts MRI sequences with contrast with our without CT fusion) acquired for planning purposes. The target is manually contoured to generate the 3D volume to irradiate, together with all the sensitive normal structures the treatment aims to spare. The treatment dose is calculated with a computerized planning system that defines the best beam arrangement to deliver the prescribed dose of radiation to the target while minimizing the dose received by non-target structures.
MD is a Clinical Research Fellow in Clinical Francesca Solda Oncology (Neuro-Oncology) at University College Hospital, London, UK. Conflicts of interest: none declared. Cornel Tancu MD MSC is a Clinical Research Fellow at the Gamma Knife Centre at QSRC, The National Hospital for Neurology and Neurosurgery, London, UK. Conflicts of interest: none declared. Neil Kitchen MD FSCR is a Consultant Neurosurgeon at the National Hospital for Neurology and Neurosurgery and Medical Director of the Gamma Knife Centre at QSRC, The National Hospital for Neurology and Neurosurgery, London, UK. Conflicts of interest: none declared. Naomi Fersht PhD MRCP FRCR is a Consultant Clinical Oncologist (Neuro-Oncology) at University College Hospital, London, UK. Conflicts of interest: none declared.
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motion tracking device to perform fractionated treatments on larger intracranial targets. While providing a very sharp dose fall-off outside the target, the technique can result in a high dose variability (inhomogeneity) within the target itself, with small areas of high dose (hot spots) in the regions of spherical dose distribution overlap. For this reason, GK RS is not routinely used to treat lesions exceeding 30 mm in maximum diameter.
Due to the large dose delivered, RS necessitates a precise positioning of the patient’s head during the entire course of the procedure. Head immobilization is achieved either with the use of invasively fixed frames or rigid thermoplastic devices with high relocation accuracy. Over the last decades, a large choice of equipment and precise treatment techniques have been implemented or refined on the base of previously existing technologies, originating an endless debate about the superiority of one radiosurgical approach over the other (Table 1). In absence of strong evidence supporting one methodology over the other, the choice of the radiation technique should be based on the lesion characteristics and on the level of expertise of the treating team.
Linac RS The linear accelerator (known as Linac) is the most commonly used device to deliver external beam radiotherapy. A Linac uses high energy X-rays (photons) to irradiate targets both in the brain and in the body. The X-rays are produced in the main body of the machine by the collision of accelerated electrons against a heavy metal target. Early Linacs initially adapted with external mechanical supports to deliver RS are now replaced by modern Linacs with high level of precision that does not require any modification for RS. The beam of photons exiting from the machine head (gantry) is directed to the target and highly focused irradiation is achieved combining multiple beams or arcs of radiation (obtained by the gantry rotation e RapidARC or VMAT radiotherapy) intersecting at the target volume. Each beam is shaped to conform to the shape of the target with multileaf collimator (MLC): an array of computer-controlled parallel leaves moving in and out to create an adjustable aperture through which the beam is delivered. The use of a dynamic MLC (the leaves move during the gantry rotation) allows to alter the intensity of the radiation during its path (intensity modulation) resulting in a more homogeneous dose distribution within targets of any shape. Invasive stereotactic frames are substituted by relocatable frames with a relocation accuracy of 1e2 mm, or precisely fitting thermoplastic masks with an accuracy of 2e3 mm. A CT planning scan is performed with the patient immobilized in the frameless device and fused with high resolution MRI imaging. The target is identified on MRI while the radiotherapy dosimetry is calculated using the CT data with the planning system defining the optimal spatial distribution of the radiotherapy beams. Sub-millimetric accuracy in dose delivery is achieved under image guidance: the target position is localized with three
Gamma knife RS The gamma knife (GK) was introduced in the late sixties and to date it represents the only dedicated device for brain RS. It consists in a multiheaded cobalt unit in which multiple cobalt-60 sources (192 in the current version) are arranged in a hemispherical distribution. The generated multiple beams of gamma radiation converge with high precision at a single point (isocentre) to achieve a circumscribed spherical dose distribution within the treatment target. The current versions of the device, Leksell GK PERFEXIONÔ and GK ICONÔ (Elekta Instrument AB, Stockholm, Sweden) (Figure 1), use collimators of 4, 8 and 16 mm diameters and have the possibility to create composite shots by combination of different diameters sectors. In the first step of the procedure, a MRI-compatible frame (Leksell G frame) is attached to the skull of the patient with four pins, under local anaesthesia. A system of fiducial markers coupled to the frame during the planning imaging allows a framebased coordinate system, where any point within the brain is located with sub millimetric precision (<0.6 mm). The number and the position of the isocentres are calculated by the planning system to shape the prescription (marginal) dose to the lesion profile (conformality). The treatment time varies according to the prescribed dose, the number and dimension of the targets. Introduced in the clinical practice in 2015, GK ICONTM has the possibility to perform frameless treatments using an integrated system of image guidance (cone beam CT) combined with a
Characteristics of radiosurgery systems Devices
Gamma knife
Linac
Robotic Linac (CyberKnife)
Tomotherapy
Proton beam
Energy
Multiple sources gamma rays 0.3 mm Rigid (frame)
Single source X-ray
Single source X-ray
Single source X-ray 1 mm Non-rigid (masks)
Single source heavy particles 1 mm Non-rigid (masks)
MLC and mMLC
Fixed collimators
Single and multiple Yes
Single and multiple Yes
Target accuracy Head immobilizati-on Beam shaping Fractionation Body RS
Multiple circular collimators Single No
1 mm 1 mm Rigid (frame) and non- Non-rigid (masks) rigid (masks) MLC and mMLC Fixed collimators IRIS Single and multiple Single and multiple Yes Yes
Table 1
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Figure 1 Leksell gamma knife Perfexion unit.
dimensional integrated imaging (cone bean CT) and matched with the planning dataset. The use of robotic treatment couches (6 degree of freedom couches) enable to correct the patient position before treatment, matching the original planning values with the information provided by the integrated imaging system. Lesions larger than 35 mm can be treated with Linac RS and hypofractionated treatments are practicable with the use of the relocatable frames.
Helical X-ray RS (Tomotherapy) A different type of image-guided brain RS can be provided on a modified linear accelerator mounted on a rotating gantry combined with a CT scanner: the Tomotherapy unit. The beam of radiation is delivered to the brain target in a helical way, obtained by the simultaneous gantry rotation and couch/patient movement during treatment. The radiation field has a fan shape and the beam intensity is altered during delivery (intensity modulation) with the use of a binary set of multileaf collimators. Accurate patient immobilization can be achieved with both invasive and non-invasive fixation devices. An integrated on board MV CT scanner allows adequate target localization and image guidance during treatment.
Robotic Linac RS (CyberKnife) The Cyberknife device is a modified Linac mounted on a robotic arm capable of movements in six degrees of freedom.4 As for conventional Linac brain RS, the patient immobilization device consists in a non-invasive frame that also allows the delivery of hypo-fractionated regimens on larger targets. The treatment planning procedures are in line with those required for conventional Linac RS (including the acquisition of a planning CT fused with diagnostic MRI images). During treatment, the robotic arm is positioned around the patient to deliver the dose through multiple beams, pre-defined by the computerize treatment plan. The freedom in movements of the robotic arm allows the delivery of a wide range of single non-coplanar beams intersecting one other to create a uniform dose distribution in the target. Each treatment beam is shaped by a circular collimator and the size of the collimator is automatically changed in course of treatment to improve the dose distribution in the target with a sharp dose fall off outside it. Correct patient positioning is continuously monitored during treatment by matching pre-treatment patient information (digitally reconstructed radiographs or DRRs) with live RX images acquired in the treatment room and generated by detectors attached to the couch. The image acquisition, together with target localization and alignment are repeated every 30e60 seconds. This allows to automatically ‘adjust’ the treatment (image guidance) by either re-orienting the robotic arm (small variations) or repositioning the patient with the movement of the automated couch (larger variations).
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Proton beam RS Proton devices are significantly less used in brain RS in comparison with the previously described equipment, but the renewed interest in proton beam radiotherapy is associated to the physic properties of this form of energy. Unlike photons, protons are able to deliver most of their energy when they hit the target. The very low entry dose and virtual no exit dose beyond the target boundaries allow to deliver the prescribed dose also to large, irregular volumes with optimal sparing of the surrounding health tissues. Protons are thus particularly appealing when the target volume is in close proximity (1 mm) with critical sensitive structures and a rapid dose fall off is needed. Protons are produced by large particle accelerators (cyclotrons or synchrotrons) where the atom is stripped of its electron to produce heavy positive charged particles. The steps involved in proton beam RS are similar to photon-based RS and relocatable frames are available for proton beam RS. Two different forms of proton beam delivery have been implemented between centres worldwide: the passive scattering system and the dynamic pencil beam scanning system. In the first, the beam of protons is spread by placing a scattering material into the path of the protons. A single scatterer broadens the beam sufficiently for treatments covering small fields while a second scatterer is generally required to ensure a uniform dose profile for larger
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large prospective observational study (OS) on patients in good KPS with up to ten lesions treated exclusively with RS demonstrated no significant difference in OS (p ¼ 0.78) between patients with a limited number of lesions (1e4 BM; OS 10.8 months; 95% CI, 9.4e12.4) and patients with 5e10 lesions (OS 10.8 months; 95% CI, 9.1e12.7). The 2012 Astro Guidelines did not make explicit recommendations for patients with more than four lesions and currently several factors, including logistic considerations, physician and patient preferences, influence the decision making process regarding treatment in this subgroup of patients. RS for BMs is currently delivered to variable doses according to the lesion/s size (from 15 to 24 Gy) (Figure 2). The dose is prescribed to the isodose surface (from 40% to 90%) encompassing the visible lesion margin (minimum dose to target). In treating multiple BMs, a single (Linac-based or tomotherapy) or a multiple isocentre (gamma knife and Cyber Knife) technique is chosen, with generally shorter treatment times achievable placing a single isocentre in the brain to treat multiple lesions simultaneously. The type of radiosurgical procedure has no impact on treatment results.
fields. A combination of custom-made collimators and compensators conforms the dose to the target. With no need of scattering materials, the pencil beam scanning technique allows coverage of complex targets using mono-energetic proton beamlets deflected magnetically to ‘scan’ the volume at different progressive depths (beam scanning). Intensity modulation of the beam is achieved modifying the output source, the speed of scanning or both.5
Patient selection for RS RS is mainly used to treat relatively small, well-circumscribed lesions. For larger treatment volumes, the incidental irradiation of the surrounding healthy structures to high doses exponentially increases the risk of developing treatment-related complications. The close proximity of sensitive structures (optic nerves, chiasm and brainstem) is also a limiting factor in delivering safely RS in view of the need to constraint the dose to these organs to lower values than those generally prescribed. Lesions located in eloquent areas of anatomical and functional importance (basal ganglia, thalamus and brainstem) deserve special attention when considering RS. The use of lower doses or hypo-fractionation is often considered when the risk of inducing vascular complications is feared. The most common delayed complication of RS is radiation necrosis: a coagulative process mainly affecting the white matter and causing clinical symptoms in 30% of treated patients. At RS doses ranging from 16 to 22 Gy, its occurrence has been reported in up to 50% of treated lesions with dose of radiation, tumour volume and location of the lesions being predictive factors for developing radio-necrosis.
Postoperative RS in brain metastases: BM can recur in up to 50% of cases after surgical resection. RS has been proposed in alternative after metastasectomy with the aim of deferring the use of WBRT to further local disseminated progression of disease and delaying its potential effects. Results from retrospective series report an overall local disease control around 80% achieved by postoperative RS on single lesions, with radio induced necrosis ranging from 0 to 6%. Large tumour cavities with consequent lower marginal doses (<16 Gy) were associated to an increased rate of local recurrence in a retrospective study on 120 patients, which also suggested the use of a 2e3 mm margin beyond the area of postoperative enhancement. The phase 2 trial on postoperative RS reported a higher incidence of local failure in originally large tumours with dural involvement.7
Clinical aspects of radiosurgery Malignant brain lesions Brain metastases: during the last two decades, RS gained a central role in treating brain metastatic disease. Its introduction in the clinical practice has progressively been encouraged in newly diagnosed and recurrent brain metastatic patients together or in alternative to whole brain irradiation (WBRT), historically offered as the only viable radiotherapy option in this group of patients, independently from their medical history and life expectancy. The success of RS relies on the rapid treatment execution, causing minimal delay in the prosecution of systemic therapies, and on the reduced impact on patient’s cognitive function in comparison with WBRT. Several randomized trials have demonstrated no survival decrement by withholding WBRT in patients with limited number (1e4) of metastases, with RS providing equivalent survival benefit to surgery in patients with single lesions. The critical selection of patients benefiting from RS is essential.6 Several prognostic scoring systems are routinely used in the clinical practice to identify suitable candidates and RS for brain metastatic disease is currently considered in patients with a life expectancy >6 months, a KPS greater or equal to 70 and controlled systemic disease. With regards to the number of brain lesions treatable, interest is growing around the possibility of considering patients with more than 3e4 metastases for RS alone, although original randomized trials evaluating the role of WBRT plus by RS versus RS alone enrolled only patients with 4 brain metastases (BM) and a maximum diameter 30 mm. A
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Benign brain lesions Meningiomas: benign meningiomas (WHO grade I) have a low risk of recurrence (about 10% at 5 years) after complete resection and are consequently managed by active monitoring with imaging. Radiotherapy is considered adjuvantly in recurrent inoperable lesions or upfront in patients not suitable for surgery in view of their medical conditions or tumour location with the aim to provide long term control of the lesions. RS is indicated as an alternative to surgery in poorly accessible lesions or adjuvantly in recurrent meningiomas with a small volume (3 cm maximum diameter, less than 10 ml in volume) and discrete margins, not involving or abutting critical structures (particularly optic tract and brainstem) and with minimal or no surrounding oedema. The range of RS doses applied varies from 12 to 18 Gy prescribed to the isodose surface (from 40% to 90%) encompassing the T1 plus gadolinium enhancing lesion on planning MRI, generally without any additional margin (Figure 3). Reported LC at 5 years after RS is in the order of 83e97% with an incidence of radio-induced complications (mainly permanent cranial nerve deficits) between 3% and 20% in most studies.8 The role of RS in atypical and anaplastic lesions is not fully defined. As higher grade meningiomas are more likely to be
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Figure 2 Multiple cerebral metastases in a patient with ovarian cancer treated by GK SRS during the same session (a, b and c). MRI scan at 6 weeks (d, e and f) showing an early response of all treated lesions in absence of perilesional oedema.
infiltrative, subclinical disease may not be adequately treated by RS. Based on the results of few, highly heterogeneous clinical reports adjuvant, RS should be judiciously considered in higher grade meningiomas or limited to the palliative setting after failure of traditional treatment modalities.
approach in the majority of patients, radiotherapy is a valuable and effective treatment for recurrent adenomas, or lesions not amenable to surgery or medical therapy. The use of RS in small (30 mm maximum diameter), wellcircumscribed residual or recurrent pituitary adenomas away from the optic pathway has been largely described in literature, with tumour control rates comparable to those achieved with fractionated radiotherapy, although long term follow up studies are still limited. A distance of at least 2 mm between the tumour and the anterior visual pathway is indicated since a dose
Pituitary adenomas are managed on a multidisciplinary level with surgery, medical therapy and radiotherapy to control symptoms secondary to mass effects and hormones hypersecretion. While trans-sphenoidal surgery is the standard initial
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Figure 3 Left sphenoid wing meningioma treated with GK SRS (15 Gy at 50% prescription isodose). The 8 Gy isodose line (green) is displayed in relation with the optic pathways. Serial MRI scans showing tumour reduction during follow-up.
dependent risk of radiation induced optic neuropathy (2%) is described for single doses of 8e12 Gy.9 In non-functioning adenomas, RS mean peripheral dose varies from 12 to 20 Gy and the reported tumour control rate is above 90% in the great majority of the studies. Treatment-related hypopituitarism (new or worsened) is the most commonly reported complication, with radio-induced optic neuropathy observed in up to 8% of patients. The rate of pituitary hormone decline after RS varies with the type of functioning tumour, and the time to reach normal hormone levels is dependent on the initial pre-treatment hormone levels. The different parameters used to describe hormonal normalization and the use of concomitant medical treatment, makes difficult to compare the large number of published studies on secreting tumours treated with RS. Furthermore a wide range of doses (15e35 Gy marginal dose) are routinely adopted through different treating Institution without a clear rational behind this practice. GH-secreting adenomas uncontrolled after surgery and/or medical therapy have similar rate of GH decline to that observed after fractionated radiotherapy (normalization of GH/IGF-I levels in 30e50% of patients at 5 years). In ACTH-secreting adenomas, time to hormonal normalization ranges from 3 months to 3 years, with a large study reporting control of hypersecretion in 70% of cases after a median 48 months. Prolactinomas are successfully treated with dopamine agonist and RS is usually reserved for patients with persistent hypersecretion following surgery. Variable rates of biochemical remission (from 15% to 83%) are described with the largest study reporting 23% of patients experiencing PRL levels normalization after a median follow up of 67.5 months.10
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Vestibular schwannomas: RS is a well-recognized primary or adjuvant treatment for small to medium size (usually <3 cm in diameter or <10 ml in volume) vestibular schwannomas (VSs) aimed to achieve tumour growth control, with functional preservation of the cranial nerves involved, mainly the facial and acoustic nerve. Koos classification has been used to help decide on the best management option, with classes IeIII on Koss classification being considered amenable to RS. Treatment of Koos IV VSs remains more controversial, with successful treatment in selected cases. Symptomatic brainstem compression or tumour volume over 10 ml are usually an indication for surgical decompression. A combined approach (partial resection followed by RS) is adopted to increase the chances of preservation of the facial nerve. Conformal dose planning requires the use of multiple small isocenters (4 and 8 mm) to improve conformality and to protect organ at risk. Current prescription doses for VS are 12e13 Gy. The median prescription isodose is around 50%, with maximum dose of 24e26 Gy inside the tumour. Some centres recommended 11 Gy for VS with functional hearing. Long-term tumour control of RS is in the order of 95% in most series (Figure 4). Long-term follow-up is required to fully evaluate treatment response (minimum 3 years) (Figure 5), with a loss of central contrast enhancement, frequently occurring between 6 and 12 months after RS, together with a transitory increase in tumour size. With current RS doses, the rate of facial nerve function preservation was up to 99%. When reported, facial palsy was often partial and transient. The rate of hearing preservation ranges between 50% and 83% but the quality of hearing before treatment plays an important role, with higher rates of functional
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Figure 4 GK planning for a Koos 3 VS treated with a prescription dose of 13 Gy at 50%. After definition of the target volume (TV) the LGP software allows the visualization in real time of the coverage, selectivity and Gradient index.
preservation in patients with an initial stage 1 of hearing loss. Trigeminal neuropathy was reported in 1e12% of patients. A net advantage of RS compared to open surgery is reported in terms of functional outcomes.11
Within the palliative setting, the use of single fraction RS and hypo-fractionated radiotherapy has been widely described in patient with recurrent high grade gliomas with good performance status, small tumour size and evidence of local progression at least 6 months after surgery. These treatments benefit is uncertain and balanced against the potential high risk carried by surgery.
RS for other brain lesions: RS has been used in small, wellcircumscribed primary tumours of various histological origin in the brain, as craniopharyngiomas, pineocytomas, haemangioblastomas and glomus jugulare tumours. These tumours are characterized by their relatively rare incidence, deep position in the brain and/or eloquent site.
Vascular brain lesions Arterio venous malformations and cavernomas: the first successful RS treatment of a cerebral arterio venous malformation (AVMs) was reported in 1972. Nowadays, RS is a recognized
Figure 5 Follow-up of a relatively large right VS (TV ¼ 7.6 ml) treated by GK RS with a prescription dose of 12 Gy at 50%. Co-registered successive MRI scans showing volume reduction at 2 and 3 years.
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Figure 6 GK planning for a left frontal unruptured AVM. The 2D images of the stereotactic catheter angiography (DSA) are defined in the same stereotactic space together with a T1-weighted with contrast and T2-weighted high-resolution MRI sequences. 22 Gy at 46% to a TV of 2 ml was prescribed in this case.
treatment of AVMs, together with endovascular treatment and surgery. RS treats small to medium size compact AVMs, those not amenable to other treatments because of their location or angio-architecture, to achieve a complete obliteration and to eliminate the long-life risk of intracranial haemorrhage (2e4% per year without treatment). Staged-volume RS is used to manage larger AVMs when unacceptable radiation-related risks due to large volumes or location are feared. Obliteration is a slow process (up to 4 years) resulting from endothelial proliferation within the abnormal blood vessel walls, supplemented by myofibroblast proliferation. This delay implies persistence of the haemorrhagic risk during the latency period and it is one of the disadvantages of RS. A planning stereotactic catheter angiography together with MRI CT scans is used in most centres for target definition (Figure 6). Historically, an initial prescription dose of 25 Gy was used, with logistic dose-response curves showing an ‘in-field’ obliteration rate superior to 80%. A recognized doseevolume relationship in developing post treatment complications has led to a dose selection depending on the volume of the malformation, ranging from 18 to 25 Gy. Overall AVM obliteration rates vary in most series between 60% and 90%. Previous embolization treatments are associated with a lower obliteration rate. Flickinger found that up to 30% of AVM patients developed new areas of T2 and FLAIR hypersignal post RS changes, at a median of 8 months after RS. Overall, 10% of the patients developed new symptoms (seizures, headache and neurologic deficit) which related to imaging changes. Most of the symptoms were transient, and the reported rate of permanent radiationrelated complication rate is 5%.
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The total volume of cerebral tissue that receives at least 12 Gy and AVM location (thalamus and brainstem being worse than cerebral hemispheres) were found to be associated with symptomatic post radiosurgery imaging changes. Although controversial, GK RS is gaining acceptance in the treatment of deep-seated cavernomas, usually with previous symptomatic haemorrhage, where it significantly reduce the risk of re-bleeding at 2 years.12 RS for functional diseases Gamma knife is the main RS platform used for functional conditions, having been initially designed by Leksell to treat these conditions. The most frequently treated disorder is represented by the trigeminal neuralgia (TN), were GK has proved to be one of the first-line treatments, independent of the existence of a neuro-vascular conflict. A high dose of radiation, between 80 and 90 Gy, is targeted in a single isocentre to the intracisternal portion of the trigeminal nerve, in average at 7.5 mm from its origin from the brainstem. The reported results from large series of patients showed 75e94% of initial significant improvement of pain. There is a risk of recurrence of pain after a mean interval of 3e4 years. The rates of mild to moderate facial hypoesthesia are 10e32% and the risk of anaesthesia dolorosa of 1e2%.13 Other functional indications of RS include: hypothalamic hamartomas causing severe refractory epilepsy (improvement of seizures 60%), thalamotomy of ventrointermedius nucleus for tremor (improvement 54%), anterior capsulotomy for refractory obsessive-compulsive disorders (improvement 55e80%) and GK ‘amygdalo-hippocampectomy’ for mesial temporal lobe epilepsy (46% improvement).
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Conclusions Several progresses have been achieved in the last decades in the technology and applicability of RS and long-term results about its benefits and risks are becoming available. A growing number of treatment indications is now under consideration and the efficacy of RS in the treatment of malignant tumours and functional disorders will need further investigations. A
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Int J Radiat Oncol Biol Phys 2014 Jan 1; 88: 130e6. PubMed PMID: 24331659. Kondziolka D, Mathieu D, Lunsford LD, et al. Radiosurgery as definitive management of intracranial meningiomas. Neurosurgery 2008 Jan; 62: 53e8. discussion 8-60. PubMed PMID: 18300891. Stafford SL, Pollock BE, Leavitt JA, et al. A study on the radiation tolerance of the optic nerves and chiasm after stereotactic radiosurgery. Int J Radiat Oncol Biol Phys 2003 Apr 1; 55: 1177e81. PubMed PMID: 12654424. Wan H, Chihiro O, Yuan S. MASEP gamma knife radiosurgery for secretory pituitary adenomas: experience in 347 consecutive cases. J Exp Clin Canc Res: CR 2009 Mar 11; 28: 36. PubMed PMID: 19284583. Pubmed Central PMCID: 2660297. Regis J, Pellet W, Delsanti C, et al. Functional outcome after gamma knife surgery or microsurgery for vestibular schwannomas. J Neurosurg 2002 Nov; 97: 1091e100. PubMed PMID: 12450031. Pollock BE. Stereotactic radiosurgery for arteriovenous malformations. Neurosurg Clin 1999 Apr; 10: 281e90. PubMed PMID: 10099093. Epub 1999/03/31. eng. Regis J, Tuleasca C, Resseguier N, et al. Long-term safety and efficacy of Gamma Knife surgery in classical trigeminal neuralgia: a 497-patient historical cohort study. J Neurosurg 2016 Apr; 124: 1079e87. PubMed PMID: 26339857.
Acknowledgment This review received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
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radiotherapy (or stereotactic radiotherapy e SRT) is the term used when the radiation is delivered over several, generally daily fractions, in a course of few days (3e5 fractions, hypofractionated radiotherapy) or few weeks (up to 33 fractions, conventionally fractionated radiotherapy).1 In conventional radiotherapy, the dose is fractionated over multiple sessions to spare the normal brain while causing optimal tumour damage and consequent treatment success. Radiation-induced cell damage mainly relies on tumour DNA double-strand damage that results in cell apoptosis (inhibition of cell repair) and reproductive cell block (inhibition of repopulation). More radio resistant tumour cells are those proliferating in absence of oxygen (lack of reoxygenation) or able to redistribute themselves within more radio-resistant phases of the cell cycle (redistribution). These radiobiological pillars e so-called ‘4Rs’ e were initially introduced to provide a means of understanding for the success or failure of fractionated radiotherapy. Later, intrinsic ‘radiosensitivity’ was added as a 5th R to explain, at the mechanistic level, the marked different radio response of different cancerous conditions.2 While explaining the mechanisms through which fractionated radiotherapy acts, the same biological considerations do not describe the effects of high single-dose/hypofractionated treatments. Direct tumour cell death is insufficient after a single high dose of radiation and might only account for the death of the more radiosensitive cells. It has been observed that a single large dose of radiation (>10 Gy) induces severe vascular damages in experimental tumours, causing secondary and additional tumour cell death. This process would consequently trigger the production of a large number of tumour antigens able to initiate an immune mediated response (usually within 1e2 weeks from treatment) that inhibits tumour cells survival and the maintenance of the correct intratumoural microenvironment.3 Although the precise mechanism behind the clinical benefit of RS is still not fully elucidated and remains largely theoretical, these experimental observations would support the responses to RS detected in both malignant, benign or vascular treated lesions.
Neurosurgical applications of radiotherapy Francesca Solda Cornel Tancu Neil Kitchen Naomi Fersht
Abstract The term ‘radiosurgery’ (RS) indicates a high precision localized technique of irradiation used as an alternative to surgical excision in patients with malignant or benign conditions, both in the brain and in the body. Brain RS has been historically identified with ‘stereotactic radiotherapy’. The term refers to the long-established neurosurgical technique of localizing the position of a lesion in the brain by using a system of external 3D co-ordinates coupled with rigid head immobilization device (often fixed to the skull). A high dose of radiation is delivered to the target stereotactically identified and a safe and accurate treatment is achieved, minimizing the dose of radiation to the surrounding brain. While for some techniques the traditional stereotactic localization has been replaced by the integration of modern imaging with non-invasive accurate immobilization, the term ‘stereotactic’ is still maintained in the clinical practice. Over the past 30 years, the implementation of powerful diagnostic imaging devices and of new radiotherapy equipment has contributed to the large diffusion of brain RS. RS plays an important role in the management of brain tumours, vascular and functional brain lesions and the expertise of the multidisciplinary treating team (clinical oncologists, neurosurgeons, neuro-radiologists and medical physics) contributes to the treatment success rate.
Keywords Gamma knife; Linac-based radiosurgery; outcome; radiosurgery; techniques
Biological background of brain radiosurgery
Radiosurgical techniques
Radiosurgery (RS) specifically refers to a radiation treatment given in a single fraction while fractionated high precise
Regardless of the technology and the techniques adopted to deliver it, brain RS aims to: accurately identify the treatment target within the brain precisely calculate the dose to deliver to the treatment target by using a computerized treatment planning system deliver precisely a high dose of radiation in one single or few (3e5) fractions minimize the dose received by the surrounding brain, hence minimizing the risk of normal tissue injury. In general, the treatment target is identified on high-resolution imaging (usually thin cuts MRI sequences with contrast with our without CT fusion) acquired for planning purposes. The target is manually contoured to generate the 3D volume to irradiate, together with all the sensitive normal structures the treatment aims to spare. The treatment dose is calculated with a computerized planning system that defines the best beam arrangement to deliver the prescribed dose of radiation to the target while minimizing the dose received by non-target structures.
MD is a Clinical Research Fellow in Clinical Francesca Solda Oncology (Neuro-Oncology) at University College Hospital, London, UK. Conflicts of interest: none declared. Cornel Tancu MD MSC is a Clinical Research Fellow at the Gamma Knife Centre at QSRC, The National Hospital for Neurology and Neurosurgery, London, UK. Conflicts of interest: none declared. Neil Kitchen MD FSCR is a Consultant Neurosurgeon at the National Hospital for Neurology and Neurosurgery and Medical Director of the Gamma Knife Centre at QSRC, The National Hospital for Neurology and Neurosurgery, London, UK. Conflicts of interest: none declared. Naomi Fersht PhD MRCP FRCR is a Consultant Clinical Oncologist (Neuro-Oncology) at University College Hospital, London, UK. Conflicts of interest: none declared.
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motion tracking device to perform fractionated treatments on larger intracranial targets. While providing a very sharp dose fall-off outside the target, the technique can result in a high dose variability (inhomogeneity) within the target itself, with small areas of high dose (hot spots) in the regions of spherical dose distribution overlap. For this reason, GK RS is not routinely used to treat lesions exceeding 30 mm in maximum diameter.
Due to the large dose delivered, RS necessitates a precise positioning of the patient’s head during the entire course of the procedure. Head immobilization is achieved either with the use of invasively fixed frames or rigid thermoplastic devices with high relocation accuracy. Over the last decades, a large choice of equipment and precise treatment techniques have been implemented or refined on the base of previously existing technologies, originating an endless debate about the superiority of one radiosurgical approach over the other (Table 1). In absence of strong evidence supporting one methodology over the other, the choice of the radiation technique should be based on the lesion characteristics and on the level of expertise of the treating team.
Linac RS The linear accelerator (known as Linac) is the most commonly used device to deliver external beam radiotherapy. A Linac uses high energy X-rays (photons) to irradiate targets both in the brain and in the body. The X-rays are produced in the main body of the machine by the collision of accelerated electrons against a heavy metal target. Early Linacs initially adapted with external mechanical supports to deliver RS are now replaced by modern Linacs with high level of precision that does not require any modification for RS. The beam of photons exiting from the machine head (gantry) is directed to the target and highly focused irradiation is achieved combining multiple beams or arcs of radiation (obtained by the gantry rotation e RapidARC or VMAT radiotherapy) intersecting at the target volume. Each beam is shaped to conform to the shape of the target with multileaf collimator (MLC): an array of computer-controlled parallel leaves moving in and out to create an adjustable aperture through which the beam is delivered. The use of a dynamic MLC (the leaves move during the gantry rotation) allows to alter the intensity of the radiation during its path (intensity modulation) resulting in a more homogeneous dose distribution within targets of any shape. Invasive stereotactic frames are substituted by relocatable frames with a relocation accuracy of 1e2 mm, or precisely fitting thermoplastic masks with an accuracy of 2e3 mm. A CT planning scan is performed with the patient immobilized in the frameless device and fused with high resolution MRI imaging. The target is identified on MRI while the radiotherapy dosimetry is calculated using the CT data with the planning system defining the optimal spatial distribution of the radiotherapy beams. Sub-millimetric accuracy in dose delivery is achieved under image guidance: the target position is localized with three
Gamma knife RS The gamma knife (GK) was introduced in the late sixties and to date it represents the only dedicated device for brain RS. It consists in a multiheaded cobalt unit in which multiple cobalt-60 sources (192 in the current version) are arranged in a hemispherical distribution. The generated multiple beams of gamma radiation converge with high precision at a single point (isocentre) to achieve a circumscribed spherical dose distribution within the treatment target. The current versions of the device, Leksell GK PERFEXIONÔ and GK ICONÔ (Elekta Instrument AB, Stockholm, Sweden) (Figure 1), use collimators of 4, 8 and 16 mm diameters and have the possibility to create composite shots by combination of different diameters sectors. In the first step of the procedure, a MRI-compatible frame (Leksell G frame) is attached to the skull of the patient with four pins, under local anaesthesia. A system of fiducial markers coupled to the frame during the planning imaging allows a framebased coordinate system, where any point within the brain is located with sub millimetric precision (<0.6 mm). The number and the position of the isocentres are calculated by the planning system to shape the prescription (marginal) dose to the lesion profile (conformality). The treatment time varies according to the prescribed dose, the number and dimension of the targets. Introduced in the clinical practice in 2015, GK ICONTM has the possibility to perform frameless treatments using an integrated system of image guidance (cone beam CT) combined with a
Characteristics of radiosurgery systems Devices
Gamma knife
Linac
Robotic Linac (CyberKnife)
Tomotherapy
Proton beam
Energy
Multiple sources gamma rays 0.3 mm Rigid (frame)
Single source X-ray
Single source X-ray
Single source X-ray 1 mm Non-rigid (masks)
Single source heavy particles 1 mm Non-rigid (masks)
MLC and mMLC
Fixed collimators
Single and multiple Yes
Single and multiple Yes
Target accuracy Head immobilizati-on Beam shaping Fractionation Body RS
Multiple circular collimators Single No
1 mm 1 mm Rigid (frame) and non- Non-rigid (masks) rigid (masks) MLC and mMLC Fixed collimators IRIS Single and multiple Single and multiple Yes Yes
Table 1
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Figure 1 Leksell gamma knife Perfexion unit.
dimensional integrated imaging (cone bean CT) and matched with the planning dataset. The use of robotic treatment couches (6 degree of freedom couches) enable to correct the patient position before treatment, matching the original planning values with the information provided by the integrated imaging system. Lesions larger than 35 mm can be treated with Linac RS and hypofractionated treatments are practicable with the use of the relocatable frames.
Helical X-ray RS (Tomotherapy) A different type of image-guided brain RS can be provided on a modified linear accelerator mounted on a rotating gantry combined with a CT scanner: the Tomotherapy unit. The beam of radiation is delivered to the brain target in a helical way, obtained by the simultaneous gantry rotation and couch/patient movement during treatment. The radiation field has a fan shape and the beam intensity is altered during delivery (intensity modulation) with the use of a binary set of multileaf collimators. Accurate patient immobilization can be achieved with both invasive and non-invasive fixation devices. An integrated on board MV CT scanner allows adequate target localization and image guidance during treatment.
Robotic Linac RS (CyberKnife) The Cyberknife device is a modified Linac mounted on a robotic arm capable of movements in six degrees of freedom.4 As for conventional Linac brain RS, the patient immobilization device consists in a non-invasive frame that also allows the delivery of hypo-fractionated regimens on larger targets. The treatment planning procedures are in line with those required for conventional Linac RS (including the acquisition of a planning CT fused with diagnostic MRI images). During treatment, the robotic arm is positioned around the patient to deliver the dose through multiple beams, pre-defined by the computerize treatment plan. The freedom in movements of the robotic arm allows the delivery of a wide range of single non-coplanar beams intersecting one other to create a uniform dose distribution in the target. Each treatment beam is shaped by a circular collimator and the size of the collimator is automatically changed in course of treatment to improve the dose distribution in the target with a sharp dose fall off outside it. Correct patient positioning is continuously monitored during treatment by matching pre-treatment patient information (digitally reconstructed radiographs or DRRs) with live RX images acquired in the treatment room and generated by detectors attached to the couch. The image acquisition, together with target localization and alignment are repeated every 30e60 seconds. This allows to automatically ‘adjust’ the treatment (image guidance) by either re-orienting the robotic arm (small variations) or repositioning the patient with the movement of the automated couch (larger variations).
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Proton beam RS Proton devices are significantly less used in brain RS in comparison with the previously described equipment, but the renewed interest in proton beam radiotherapy is associated to the physic properties of this form of energy. Unlike photons, protons are able to deliver most of their energy when they hit the target. The very low entry dose and virtual no exit dose beyond the target boundaries allow to deliver the prescribed dose also to large, irregular volumes with optimal sparing of the surrounding health tissues. Protons are thus particularly appealing when the target volume is in close proximity (1 mm) with critical sensitive structures and a rapid dose fall off is needed. Protons are produced by large particle accelerators (cyclotrons or synchrotrons) where the atom is stripped of its electron to produce heavy positive charged particles. The steps involved in proton beam RS are similar to photon-based RS and relocatable frames are available for proton beam RS. Two different forms of proton beam delivery have been implemented between centres worldwide: the passive scattering system and the dynamic pencil beam scanning system. In the first, the beam of protons is spread by placing a scattering material into the path of the protons. A single scatterer broadens the beam sufficiently for treatments covering small fields while a second scatterer is generally required to ensure a uniform dose profile for larger
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large prospective observational study (OS) on patients in good KPS with up to ten lesions treated exclusively with RS demonstrated no significant difference in OS (p ¼ 0.78) between patients with a limited number of lesions (1e4 BM; OS 10.8 months; 95% CI, 9.4e12.4) and patients with 5e10 lesions (OS 10.8 months; 95% CI, 9.1e12.7). The 2012 Astro Guidelines did not make explicit recommendations for patients with more than four lesions and currently several factors, including logistic considerations, physician and patient preferences, influence the decision making process regarding treatment in this subgroup of patients. RS for BMs is currently delivered to variable doses according to the lesion/s size (from 15 to 24 Gy) (Figure 2). The dose is prescribed to the isodose surface (from 40% to 90%) encompassing the visible lesion margin (minimum dose to target). In treating multiple BMs, a single (Linac-based or tomotherapy) or a multiple isocentre (gamma knife and Cyber Knife) technique is chosen, with generally shorter treatment times achievable placing a single isocentre in the brain to treat multiple lesions simultaneously. The type of radiosurgical procedure has no impact on treatment results.
fields. A combination of custom-made collimators and compensators conforms the dose to the target. With no need of scattering materials, the pencil beam scanning technique allows coverage of complex targets using mono-energetic proton beamlets deflected magnetically to ‘scan’ the volume at different progressive depths (beam scanning). Intensity modulation of the beam is achieved modifying the output source, the speed of scanning or both.5
Patient selection for RS RS is mainly used to treat relatively small, well-circumscribed lesions. For larger treatment volumes, the incidental irradiation of the surrounding healthy structures to high doses exponentially increases the risk of developing treatment-related complications. The close proximity of sensitive structures (optic nerves, chiasm and brainstem) is also a limiting factor in delivering safely RS in view of the need to constraint the dose to these organs to lower values than those generally prescribed. Lesions located in eloquent areas of anatomical and functional importance (basal ganglia, thalamus and brainstem) deserve special attention when considering RS. The use of lower doses or hypo-fractionation is often considered when the risk of inducing vascular complications is feared. The most common delayed complication of RS is radiation necrosis: a coagulative process mainly affecting the white matter and causing clinical symptoms in 30% of treated patients. At RS doses ranging from 16 to 22 Gy, its occurrence has been reported in up to 50% of treated lesions with dose of radiation, tumour volume and location of the lesions being predictive factors for developing radio-necrosis.
Postoperative RS in brain metastases: BM can recur in up to 50% of cases after surgical resection. RS has been proposed in alternative after metastasectomy with the aim of deferring the use of WBRT to further local disseminated progression of disease and delaying its potential effects. Results from retrospective series report an overall local disease control around 80% achieved by postoperative RS on single lesions, with radio induced necrosis ranging from 0 to 6%. Large tumour cavities with consequent lower marginal doses (<16 Gy) were associated to an increased rate of local recurrence in a retrospective study on 120 patients, which also suggested the use of a 2e3 mm margin beyond the area of postoperative enhancement. The phase 2 trial on postoperative RS reported a higher incidence of local failure in originally large tumours with dural involvement.7
Clinical aspects of radiosurgery Malignant brain lesions Brain metastases: during the last two decades, RS gained a central role in treating brain metastatic disease. Its introduction in the clinical practice has progressively been encouraged in newly diagnosed and recurrent brain metastatic patients together or in alternative to whole brain irradiation (WBRT), historically offered as the only viable radiotherapy option in this group of patients, independently from their medical history and life expectancy. The success of RS relies on the rapid treatment execution, causing minimal delay in the prosecution of systemic therapies, and on the reduced impact on patient’s cognitive function in comparison with WBRT. Several randomized trials have demonstrated no survival decrement by withholding WBRT in patients with limited number (1e4) of metastases, with RS providing equivalent survival benefit to surgery in patients with single lesions. The critical selection of patients benefiting from RS is essential.6 Several prognostic scoring systems are routinely used in the clinical practice to identify suitable candidates and RS for brain metastatic disease is currently considered in patients with a life expectancy >6 months, a KPS greater or equal to 70 and controlled systemic disease. With regards to the number of brain lesions treatable, interest is growing around the possibility of considering patients with more than 3e4 metastases for RS alone, although original randomized trials evaluating the role of WBRT plus by RS versus RS alone enrolled only patients with 4 brain metastases (BM) and a maximum diameter 30 mm. A
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Benign brain lesions Meningiomas: benign meningiomas (WHO grade I) have a low risk of recurrence (about 10% at 5 years) after complete resection and are consequently managed by active monitoring with imaging. Radiotherapy is considered adjuvantly in recurrent inoperable lesions or upfront in patients not suitable for surgery in view of their medical conditions or tumour location with the aim to provide long term control of the lesions. RS is indicated as an alternative to surgery in poorly accessible lesions or adjuvantly in recurrent meningiomas with a small volume (3 cm maximum diameter, less than 10 ml in volume) and discrete margins, not involving or abutting critical structures (particularly optic tract and brainstem) and with minimal or no surrounding oedema. The range of RS doses applied varies from 12 to 18 Gy prescribed to the isodose surface (from 40% to 90%) encompassing the T1 plus gadolinium enhancing lesion on planning MRI, generally without any additional margin (Figure 3). Reported LC at 5 years after RS is in the order of 83e97% with an incidence of radio-induced complications (mainly permanent cranial nerve deficits) between 3% and 20% in most studies.8 The role of RS in atypical and anaplastic lesions is not fully defined. As higher grade meningiomas are more likely to be
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Figure 2 Multiple cerebral metastases in a patient with ovarian cancer treated by GK SRS during the same session (a, b and c). MRI scan at 6 weeks (d, e and f) showing an early response of all treated lesions in absence of perilesional oedema.
infiltrative, subclinical disease may not be adequately treated by RS. Based on the results of few, highly heterogeneous clinical reports adjuvant, RS should be judiciously considered in higher grade meningiomas or limited to the palliative setting after failure of traditional treatment modalities.
approach in the majority of patients, radiotherapy is a valuable and effective treatment for recurrent adenomas, or lesions not amenable to surgery or medical therapy. The use of RS in small (30 mm maximum diameter), wellcircumscribed residual or recurrent pituitary adenomas away from the optic pathway has been largely described in literature, with tumour control rates comparable to those achieved with fractionated radiotherapy, although long term follow up studies are still limited. A distance of at least 2 mm between the tumour and the anterior visual pathway is indicated since a dose
Pituitary adenomas are managed on a multidisciplinary level with surgery, medical therapy and radiotherapy to control symptoms secondary to mass effects and hormones hypersecretion. While trans-sphenoidal surgery is the standard initial
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Figure 3 Left sphenoid wing meningioma treated with GK SRS (15 Gy at 50% prescription isodose). The 8 Gy isodose line (green) is displayed in relation with the optic pathways. Serial MRI scans showing tumour reduction during follow-up.
dependent risk of radiation induced optic neuropathy (2%) is described for single doses of 8e12 Gy.9 In non-functioning adenomas, RS mean peripheral dose varies from 12 to 20 Gy and the reported tumour control rate is above 90% in the great majority of the studies. Treatment-related hypopituitarism (new or worsened) is the most commonly reported complication, with radio-induced optic neuropathy observed in up to 8% of patients. The rate of pituitary hormone decline after RS varies with the type of functioning tumour, and the time to reach normal hormone levels is dependent on the initial pre-treatment hormone levels. The different parameters used to describe hormonal normalization and the use of concomitant medical treatment, makes difficult to compare the large number of published studies on secreting tumours treated with RS. Furthermore a wide range of doses (15e35 Gy marginal dose) are routinely adopted through different treating Institution without a clear rational behind this practice. GH-secreting adenomas uncontrolled after surgery and/or medical therapy have similar rate of GH decline to that observed after fractionated radiotherapy (normalization of GH/IGF-I levels in 30e50% of patients at 5 years). In ACTH-secreting adenomas, time to hormonal normalization ranges from 3 months to 3 years, with a large study reporting control of hypersecretion in 70% of cases after a median 48 months. Prolactinomas are successfully treated with dopamine agonist and RS is usually reserved for patients with persistent hypersecretion following surgery. Variable rates of biochemical remission (from 15% to 83%) are described with the largest study reporting 23% of patients experiencing PRL levels normalization after a median follow up of 67.5 months.10
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Vestibular schwannomas: RS is a well-recognized primary or adjuvant treatment for small to medium size (usually <3 cm in diameter or <10 ml in volume) vestibular schwannomas (VSs) aimed to achieve tumour growth control, with functional preservation of the cranial nerves involved, mainly the facial and acoustic nerve. Koos classification has been used to help decide on the best management option, with classes IeIII on Koss classification being considered amenable to RS. Treatment of Koos IV VSs remains more controversial, with successful treatment in selected cases. Symptomatic brainstem compression or tumour volume over 10 ml are usually an indication for surgical decompression. A combined approach (partial resection followed by RS) is adopted to increase the chances of preservation of the facial nerve. Conformal dose planning requires the use of multiple small isocenters (4 and 8 mm) to improve conformality and to protect organ at risk. Current prescription doses for VS are 12e13 Gy. The median prescription isodose is around 50%, with maximum dose of 24e26 Gy inside the tumour. Some centres recommended 11 Gy for VS with functional hearing. Long-term tumour control of RS is in the order of 95% in most series (Figure 4). Long-term follow-up is required to fully evaluate treatment response (minimum 3 years) (Figure 5), with a loss of central contrast enhancement, frequently occurring between 6 and 12 months after RS, together with a transitory increase in tumour size. With current RS doses, the rate of facial nerve function preservation was up to 99%. When reported, facial palsy was often partial and transient. The rate of hearing preservation ranges between 50% and 83% but the quality of hearing before treatment plays an important role, with higher rates of functional
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Figure 4 GK planning for a Koos 3 VS treated with a prescription dose of 13 Gy at 50%. After definition of the target volume (TV) the LGP software allows the visualization in real time of the coverage, selectivity and Gradient index.
preservation in patients with an initial stage 1 of hearing loss. Trigeminal neuropathy was reported in 1e12% of patients. A net advantage of RS compared to open surgery is reported in terms of functional outcomes.11
Within the palliative setting, the use of single fraction RS and hypo-fractionated radiotherapy has been widely described in patient with recurrent high grade gliomas with good performance status, small tumour size and evidence of local progression at least 6 months after surgery. These treatments benefit is uncertain and balanced against the potential high risk carried by surgery.
RS for other brain lesions: RS has been used in small, wellcircumscribed primary tumours of various histological origin in the brain, as craniopharyngiomas, pineocytomas, haemangioblastomas and glomus jugulare tumours. These tumours are characterized by their relatively rare incidence, deep position in the brain and/or eloquent site.
Vascular brain lesions Arterio venous malformations and cavernomas: the first successful RS treatment of a cerebral arterio venous malformation (AVMs) was reported in 1972. Nowadays, RS is a recognized
Figure 5 Follow-up of a relatively large right VS (TV ¼ 7.6 ml) treated by GK RS with a prescription dose of 12 Gy at 50%. Co-registered successive MRI scans showing volume reduction at 2 and 3 years.
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Figure 6 GK planning for a left frontal unruptured AVM. The 2D images of the stereotactic catheter angiography (DSA) are defined in the same stereotactic space together with a T1-weighted with contrast and T2-weighted high-resolution MRI sequences. 22 Gy at 46% to a TV of 2 ml was prescribed in this case.
treatment of AVMs, together with endovascular treatment and surgery. RS treats small to medium size compact AVMs, those not amenable to other treatments because of their location or angio-architecture, to achieve a complete obliteration and to eliminate the long-life risk of intracranial haemorrhage (2e4% per year without treatment). Staged-volume RS is used to manage larger AVMs when unacceptable radiation-related risks due to large volumes or location are feared. Obliteration is a slow process (up to 4 years) resulting from endothelial proliferation within the abnormal blood vessel walls, supplemented by myofibroblast proliferation. This delay implies persistence of the haemorrhagic risk during the latency period and it is one of the disadvantages of RS. A planning stereotactic catheter angiography together with MRI CT scans is used in most centres for target definition (Figure 6). Historically, an initial prescription dose of 25 Gy was used, with logistic dose-response curves showing an ‘in-field’ obliteration rate superior to 80%. A recognized doseevolume relationship in developing post treatment complications has led to a dose selection depending on the volume of the malformation, ranging from 18 to 25 Gy. Overall AVM obliteration rates vary in most series between 60% and 90%. Previous embolization treatments are associated with a lower obliteration rate. Flickinger found that up to 30% of AVM patients developed new areas of T2 and FLAIR hypersignal post RS changes, at a median of 8 months after RS. Overall, 10% of the patients developed new symptoms (seizures, headache and neurologic deficit) which related to imaging changes. Most of the symptoms were transient, and the reported rate of permanent radiationrelated complication rate is 5%.
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The total volume of cerebral tissue that receives at least 12 Gy and AVM location (thalamus and brainstem being worse than cerebral hemispheres) were found to be associated with symptomatic post radiosurgery imaging changes. Although controversial, GK RS is gaining acceptance in the treatment of deep-seated cavernomas, usually with previous symptomatic haemorrhage, where it significantly reduce the risk of re-bleeding at 2 years.12 RS for functional diseases Gamma knife is the main RS platform used for functional conditions, having been initially designed by Leksell to treat these conditions. The most frequently treated disorder is represented by the trigeminal neuralgia (TN), were GK has proved to be one of the first-line treatments, independent of the existence of a neuro-vascular conflict. A high dose of radiation, between 80 and 90 Gy, is targeted in a single isocentre to the intracisternal portion of the trigeminal nerve, in average at 7.5 mm from its origin from the brainstem. The reported results from large series of patients showed 75e94% of initial significant improvement of pain. There is a risk of recurrence of pain after a mean interval of 3e4 years. The rates of mild to moderate facial hypoesthesia are 10e32% and the risk of anaesthesia dolorosa of 1e2%.13 Other functional indications of RS include: hypothalamic hamartomas causing severe refractory epilepsy (improvement of seizures 60%), thalamotomy of ventrointermedius nucleus for tremor (improvement 54%), anterior capsulotomy for refractory obsessive-compulsive disorders (improvement 55e80%) and GK ‘amygdalo-hippocampectomy’ for mesial temporal lobe epilepsy (46% improvement).
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Conclusions Several progresses have been achieved in the last decades in the technology and applicability of RS and long-term results about its benefits and risks are becoming available. A growing number of treatment indications is now under consideration and the efficacy of RS in the treatment of malignant tumours and functional disorders will need further investigations. A
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Int J Radiat Oncol Biol Phys 2014 Jan 1; 88: 130e6. PubMed PMID: 24331659. Kondziolka D, Mathieu D, Lunsford LD, et al. Radiosurgery as definitive management of intracranial meningiomas. Neurosurgery 2008 Jan; 62: 53e8. discussion 8-60. PubMed PMID: 18300891. Stafford SL, Pollock BE, Leavitt JA, et al. A study on the radiation tolerance of the optic nerves and chiasm after stereotactic radiosurgery. Int J Radiat Oncol Biol Phys 2003 Apr 1; 55: 1177e81. PubMed PMID: 12654424. Wan H, Chihiro O, Yuan S. MASEP gamma knife radiosurgery for secretory pituitary adenomas: experience in 347 consecutive cases. J Exp Clin Canc Res: CR 2009 Mar 11; 28: 36. PubMed PMID: 19284583. Pubmed Central PMCID: 2660297. Regis J, Pellet W, Delsanti C, et al. Functional outcome after gamma knife surgery or microsurgery for vestibular schwannomas. J Neurosurg 2002 Nov; 97: 1091e100. PubMed PMID: 12450031. Pollock BE. Stereotactic radiosurgery for arteriovenous malformations. Neurosurg Clin 1999 Apr; 10: 281e90. PubMed PMID: 10099093. Epub 1999/03/31. eng. Regis J, Tuleasca C, Resseguier N, et al. Long-term safety and efficacy of Gamma Knife surgery in classical trigeminal neuralgia: a 497-patient historical cohort study. J Neurosurg 2016 Apr; 124: 1079e87. PubMed PMID: 26339857.
Acknowledgment This review received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
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Ó 2018 Published by Elsevier Ltd.
Please cite this article in press as: Solda F, et al., Neurosurgical applications of radiotherapy, Surgery (2018), https://doi.org/10.1016/ j.mpsur.2018.09.008