Radiosurgery for pituitary adenomas

Radiotherapy has been successfully employed in the management of patients with pituitary adenoma. It achieves excellent long-term tumour control and frequently leads to normalization of elevated serum hormone concentrations, albeit with delay. There are well documented late effects of irradiation of which hypothalamic–pituitary insufficiency is the most frequent. Serious late complications are uncommon with overall risk generally < 2%. Nevertheless, the perception, largely based on selected studies of early use of radiation, is that radiotherapy is damaging and the effectiveness is questioned. Into this scenario comes radiosurgery offering an apparent quantum leap in radiation technology that combines neurosurgical terminology of surgery and stereotaxy with more advanced means of radiation delivery. The impression is of surgical precision added to the science of radiation. Have the new techniques altered the management of patients with pituitary adenoma or is the new technology the emperor's new clothes? In an attempt to provide an objective answer we present a systematic review of the literature published between 1985 and 2003 on the efficacy of radiosurgery in patients with pituitary adenomas and at least 6 months’ follow-up excluding single case reports and nonpeer-reviewed chapters. As critical interpretation of these data requires both an understanding of current radiotherapy technology and the improvements and the results of conventional treatment, they are discussed first. The aim of modern techniques is to achieve localized radiation delivery. Three principal advances have enabled this: (i) improvement in patient immobilization, (ii) modern imaging combined with precise image co-registration and (iii) more localized means of giving radiation aided by three-dimensional (3D) planning. Despite the perception that it is the technique of delivery which is the major determinant of modern localized radiotherapy, it is the combination of better immobilization and high-definition co-registered 3D imaging which is responsible for most of the gain in sparing normal tissue. In conventional radiotherapy, patients are usually immobilized in an individually shaped plastic mask. The head has some freedom to move (3–5 mm; Gildersleve et al., 1995) and to avoid missing the tumour as a result of the movement during a course of fractionated radiotherapy a safety margin is included in planning. Better immobilization is achieved through more precise and firmer fixation with relocatable frames (Gill et al., 1991; Graham et al., 1991) and more precise fitting mask systems (Karger et al., 2001). The usual gain is an improvement in relocation accuracy to 1–2 mm for relocatable frames and 2–3 mm for mask systems allowing for a smaller margin. Invasive neurosurgical type frames are used for single fraction radiosurgery with ≤ 1 mm accuracy. Stereotactic techniques initially adopted from neurosurgery have enabled more precise localization of tumours and critical neural structures. Pituitary adenoma position is described using 3D co-ordinates defined from external markers (fiducial markers). Fixed internal anatomical structures may be used to define the 3D space and fiducial markers may in the future become redundant. Tumour localization has also improved using data from CT and MRI which are co-registered. The extent of the adenoma and the position of critical structures such as the optic chiasm and nerves are best localized on MRI while co-registered CT scans provide the appropriate X-ray absorption information for radiotherapy planning. Radiotherapy planning has also independently improved with the use of 3D displays and 3D methods of calculation of dose distribution. It is therefore relatively easy to depart from the arrangement of three fixed fields in a single plane used in conventional radiotherapy. It is axiomatic that high precision treatment delivery with little margin for error demands that all parts of the tumour are identified and treated. Expert neuroradiology interpretation has therefore become an essential component of modern radiotherapy practice. Nevertheless, rapid advances in imaging often outstrip image interpretation which, at times, inevitably becomes subjective and compares unfavourably with accuracy demanded of the precision radiotherapy technique. Pragmatically, a reasonable and safe approach is to accept regions of ‘uncertainty’ as representing potential tumour involvement, providing inclusion does not result in unacceptable treatment toxicity. The aim of all high precision techniques is to minimize the radiation to normal tissue for equivalent dose of radiation to the target. There are two ways of achieving it. Shaping the radiation beams to conform to the shape of the tumour reduces radiation exposure to surrounding normal brain and this is the principle of conformal radiotherapy. Increasing the number of beams is believed to lead to a greater dose differential between the target and surrounding normal tissue with further normal tissue sparing. Linear accelerator beams can be shaped with lead alloy blocks mounted onto an external tray or by altering the shape of the aperture at linear accelerator head with a multileaf collimator (MLC). This results in the reduction in volume of normal brain receiving high doses of radiation when compared to square or rectangular beams (Kaushal et al., 1990). The available MLCs consist of individual leaves of 3 mm (micro-MLC), 5 mm (mini-MLC) and 10 mm (conventional) width. The leaves are automatically positioned to predefined shapes based on information transferred directly from the planning computer. There are little data to demonstrate a difference in normal tissue sparing between 3 mm or 5 mm leaves. High precision conformal radiation using stereotactic techniques which includes better immobilization, imaging and conformation, is described as stereotactic conformal radiotherapy (SCRT) and is usually delivered as fractionated treatment. Using more than three beams separated in space reduces the amount of normal brain receiving high radiation doses but this is at the cost of increasing the volume of brain receiving low doses. The benefit for increasing the number of beams is, however, only seen for arrangement of four to six beams. Although there is a perception that higher number of beams improves dose differential, studies of 3D dose distribution demonstrate not only lack of further normal tissue sparing but, frequently, detriment at high dose levels for more than six beams (Perks et al., 1999; Ajithkumar et al., submitted). Techniques of dynamic shaping with MLC leaves adjusting to the tumour shape during rotation of the linear accelerator around the tumour are, on present evidence, also no better than a four to six fixed field technique (Solberg et al., 2001; Ajithkumar et al., submitted). In modern radiotherapy practice, MLC leaves can be used to modulate the intensity as well as altering the shape of the radiation beam and this is described as intensity modulated radiotherapy (IMRT). Studies of dose distribution in tumour and normal tissue show no benefit for IMRT compared to fixed field SCRT in the treatment of pituitary adenoma (Khoo et al., 1999; Low et al., in preparation). The technique of focussed radiation with multiple cobalt sources was developed by Leksel prior to the routine use of linear accelerators which superceded cobalt as the high energy radiation source. In multiheaded cobalt unit [gamma knife (GK)], 201 cobalt sources are arranged in a hemisphere and focussed with a collimator helmet onto a central target. This results in small spherical high dose volumes ranging from 6 to 18 mm diameter. Multiple radiation spheres are combined in a multiple isocentre technique to conform to the shape of larger and nonspherical tumours which would include the majority of pituitary adenomas considered suitable for radiation treatment. Computerized 3D planning determines the optimum number and distribution of isocentres and this can be aided by selective occlusion (plugging) of collimator apertures. GK irradiation performed as a single treatment given with a patient immobilized in a fixed frame is described as stereotactic radiosurgery (SRS). The only published comparison of GK multiple isocentre techniques and linear accelerator multiple fixed field treatment shows no clear advantage for either of the techniques in terms of sparing of normal tissue receiving high radiation doses (Yu et al., 1999). The wide spatial separation of GK sources leads to an increase in the volume of normal brain receiving low doses, although the clinical significance is at present not clear. With GK, overlapping radiation spheres of multiple isocentres produce small high-dose regions (hot spots). This may not be of clinical relevance in terms of toxicity if there are no normal structures within the target. Multiple isocentre treatment of tumours involving the cavernous sinus or the optic apparatus (or in close proximity to them) may produce hot spots in cranial nerves, with a risk of late radiation damage. In the early days of radiosurgery, linear accelerators were adapted to mimic GK dose distribution through multiple arcs of rotation equivalent to hemispheric distribution of radiation sources (sometimes described as SMART). This produces spherical high-dose volumes which are not size limited. For the treatment of nonspherical lesions, conformation can be achieved with multiple isocentre technique similar to the GK technique. Such treatment on a linear accelerator is highly time- and manpower-intensive. The four to six conformal fixed field technique produces superior dose distribution within and outside the target (Laing et al., 1993) and has largely superseded multiple arc multiple isocentre technique. In summary, GK SRS and linear accelerator SCRT treat similar volumes of normal brain to high radiation doses. GK SRS produces dose inhomogeneity within the target and increases the volume of normal brain receiving low radiation doses (1–5%); linear accelerator SCRT increases the volumes of medium–low doses (20–30%). The only claimed benefit of GK SRS over linear accelerator SCRT is precision of single treatment compared to the small inaccuracy of relocation of immobilization device with multiple treatments. The principal difference between SRS and SCRT is in the number of radiation treatments. The term radiosurgery is reserved for radiation given in one large dose (single fraction) and the term radiotherapy is used for treatment given in multiple, usually daily, doses (fractionated treatment). The term fractionated radiosurgery is an attempt to cash in on the apparent marketing superiority of ‘radiosurgery’ over ‘radiotherapy’ and is inappropriate. The initial rationale for single fraction radiosurgery was based on the perception of single high radiation dose as a surgical tool causing tissue destruction. There is little doubt that a large single dose of radiation results in a higher cell kill than the same dose given in a number of small fractions. It is, however, the differential effect between tumour and normal tissue damage embodied in the concept of therapeutic ratio, which should provide the measure for comparing the efficacy of treatments. In this respect, large single doses of radiation are more toxic to normal tissue, particularly the brain, than similar doses given in a fractionated manner. Given that the majority of pituitary adenomas lie in close proximity to the optic apparatus and the nerves of the cavernous sinus, it is perhaps not surprising that early enthusiastic use of high-dose SRS for large pituitary adenomas containing the optic apparatus led to an unacceptably high incidence of optic radiation neuropathy (Rocher et al., 1995). As the risk of radiation optic neuropathy following SRS is dose-dependent (Tishler et al., 1993; Leber et al., 1998), current practice aims to avoid irradiating the optic apparatus beyond single doses of 8–10 Gy. This means limiting radiosurgery to small adenomas away from the optic apparatus (usually ≥ 5 mm) and using lower doses which do not cause tissue ablation. The belief in the benefit of single fraction radiosurgery for pituitary adenoma and, for that matter, other benign tumours, has also been based on radiobiological formalism which defines equivalent doses and fractionation schemes through biologically derived models (Gutin et al., 1991; Steel, 1993). While such models may be appropriate for malignant tumours when the number of radiation fractions changes, they are not validated for single fraction treatment and biological constants necessary to calculate such equivalent doses do not exist for benign tumours. Publications claiming theoretical benefit of single fraction radiosurgery over fractionated irradiation (Larson et al., 1993) are based on constants not derived from experimental data and may therefore be misleading. There are several important caveats in the critical interpretation of data in clinical studies of the efficacy of radiation treatment of pituitary adenoma. The first relates to the endpoints. While effectiveness may be best assessed in terms of survival, tumour control (as actuarial progression free survival) and quality of life (QOL) information on the effect of different treatment modalities on survival and QOL is limited and the main reported efficacy endpoints in patients with nonfunctioning pituitary adenoma are progression-free survival (PFS) and late morbidity. In patients with secreting tumours, the principal endpoints used are the normalization of elevated hormone concentrations and long-term tumour control. The delay in achieving normal hormonal status is largely related to pretreatment hormone levels; the higher the pretreatment concentration, the longer it will take to normalize. To assess the rate of decline it is therefore necessary to either incorporate individual patient data or make it independent of the initial level. One appropriate measure is the time necessary to reach 50% of initial hormone level. Results of SRS are frequently reported as ‘control rate’ without the dimension of time, failing to take into account the duration of follow-up of individual patients. Such data, although at first glance appealing, do not provide the appropriate measure of efficacy and are potentially misleading. The second caveat is that basic radiobiological considerations (discussed above) introduce case selection bias. Conventional external beam radiotherapy to doses of in fractions is the conventional radiation of surrounding normal structures the optic there is no to the size of pituitary adenoma suitable for dose fractionated radiotherapy and all reported include not only tumours but also often large adenomas with frequently or in close proximity to the optic The damaging effect of large single doses of radiation to critical normal structures that patients with SRS have small tumours well away from the optic The is an that the majority of are single studies and as radiation is individual may have a necessary in the to and bias. The reported in large of conventional external beam radiotherapy for pituitary adenoma is et al., et al., et al., et al., 1993; et al., et al., et al., In the of over the was at 10 and at et al., 1993). In the rate of reduction of conventional is a 50% in et al., It has also been as of in a of patients in et al., The rate of reduction of is with normalization in of patients treatment et al., In the normalization of and has been reported in of patients. of in all patients radiotherapy, with the majority in the first treatment et al., There is limited information the rate of decline of as radiotherapy is used as the treatment for The toxicity of fractionated external beam radiotherapy is with risk of radiation optic neuropathy et al., 1993; et al., and risk of of normal brain structures et al., Although radiation is for potential there is no clear that fractionated irradiation beyond the effect of surgery and the pituitary adenoma et al., et al., The most late of radiation is to be to In patients with normal pituitary around the time of radiotherapy, hormone is in of patients at 10 The most late effect of radiation for pituitary adenoma is the of second brain The reported is in the of at et al., et al., 1993; et al., 2001). Although there is an incidence of and in patients with pituitary adenoma with radiation, the of radiation on is not defined et al., et al., 2001; et al., 1985 and studies involving patients with GK radiosurgery were reported either as or to the of GK, 18 patients radiosurgery for pituitary adenoma from around the to clinical assessed was data were not the reported endpoints of efficacy in individual studies were included hormonal normalization for tumours and As summary, measure at a time for initial size was For hormonal and methods and reported were SRS data for patients have been reported in The follow-up from 6 to of serum concentrations were reported for patients six normal serum concentrations prior to In patients concentrations in three they and in six they was not reported in the patients. to from 3 to In summary, at a follow-up of only of patients normalization of serum In an early of patients with with GK the time to normal serum was than in a control of patients with conventional fractionated et al., As SRS patients lower pretreatment concentrations some were than it is therefore not to that the rate of decline for the two techniques of irradiation is more reported in serum concentrations in patients 50% of treatment with a reduction in levels et al., and this is in the same as following fractionated radiotherapy. SRS data have been reported for patients in The follow-up from 6 to of patients normalization of hormone increase in hormone and was not reported in the to hormonal from 6 to 3 a follow-up of of patients normalization of elevated hormone which a decline than seen following conventional treatment. following SRS have been reported for patients with in The follow-up from 6 to The serum concentrations in patients in and were in concentrations in patients and no data are available for the The rate of hormone decline studies involving patients reported time to hormonal or ranging from 5 to The time to hormone normalization is we that follow-up time reported the only of patients normalization of at a follow-up of The results of SRS have been reported for patients with nonfunctioning pituitary adenoma in studies reported a ‘control rate’ of more than without time or of follow-up et al., et al., 1999; et al., et al., One reported a relatively of in a of patients with both and tumours. was reported in of patients at an overall follow-up of et al., et al., et al., et al., 2001; et al., et al., In complications were not or There is no for decline of elevated hormone concentrations following GK SRS than has been reported conventional Studies that take into account individual hormone concentrations show similar decline et al., et al., The majority of reports do not provide appropriate information to assess the efficacy of GK radiosurgery in terms of tumour control in either or nonfunctioning pituitary the published only one reported actuarial et al., of follow-up and patient selection there is information late although individual have been review of early which was (Rocher et al., only three studies of linear accelerator SRS et al., et al., et al., et reported patients with a single fraction SRS to a dose of and for ≥ 6 with and no but serum concentrations within in patients with et al., et al., In a of patients with pituitary adenoma < 3 of patients with and two of two patients with combined and tumours normal hormone within 1 although some patients normal levels prior to SRS et al., tumour control was not of patients developed hormone and linear accelerator In the of et the tumour control rate of 18 patients in this was patients radiotherapy. of patients with secreting tumours hormonal normalization at a of Three patients developed radiation of the and patients new hormonal et al., In summary, the reported literature of linear accelerator SRS is limited. the results published are equivalent to reported for GK with little information on long-term tumour control and no clear of decline in hormone There are four published reports of SCRT in patients with pituitary adenoma et al., et al., et al., et al., 2001). control in and was in patients et al., at a follow-up of 10 and at 3 in patients et al., of elevated hormone concentrations was reported in over 50% patients within a of 18 of patients new hormone et al., In a of was at a follow-up of et al., 2001). of patients with secreting adenomas normalization and a reduction in serum hormone The actuarial progression-free and overall survival in the of patients nonfunctioning and was hormone was in patients et al., of patients with follow-up for 3 shows a and actuarial The early results of linear accelerator SCRT are within the reported for conventional radiotherapy. The follow-up does not for long-term efficacy or late While the of stereotactic radiotherapy may into a clinical benefit in terms of long-term this has not been and will of follow-up and larger to small of patients with pituitary adenoma radiotherapy. with further radiation has been considered of damaging effect of radiation on normal brain, particularly optic chiasm and Stereotactic techniques the of irradiation of structures providing they are not in close proximity to the tumour and both SRS and SCRT have been used in this to high precision it is that there is of radiation damage when first treatment was to doses conventional radiation This means that late 5 or following conventional doses of in fractions can be relatively to more or the same dose with small risk of radiation optic neuropathy using conventional techniques et al., et al., Nevertheless, SCRT can further the dose to the optic apparatus and we have used it in 10 patients with tumours irradiation without late effects data are not as in has to be to tumours away from the optic chiasm and SRS has been employed as an treatment in patients with elevated hormone The rate of decline of elevated hormone levels is similar to that seen following SRS as with no reported radiation optic neuropathy et al., The available data do not provide information on the efficacy of with SRS or SCRT on long-term tumour or hormonal control. from conventional fractionated treatment that fractionated treatment has efficacy and toxicity et al., et al., advances have improved the delivery of radiation to tumours with reduction in radiation dose to the normal brain to higher radiation doses during radiotherapy of pituitary adenoma is a reasonable in and may in the future into a clinical enthusiastic should be by The on precision technology without into account the subjective of interpretation of modern the risk of missing parts of the tumour included in larger radiation fields used in conventional The the of or linear and fractionation of treatment and largely by and the there is little to the for the superiority of GK radiosurgery over fractionated conventional or stereotactic radiotherapy. The of data on for in the use of single fraction radiosurgery to achieve long-term tumour control. The for decline of elevated hormone concentrations in patients with secreting tumours The only in of SRS for secreting tumours are by small and well away from the optic is of single fraction treatment. There is a for studies to define the long-term efficacy and toxicity of particularly in comparison to fractionated conventional and stereotactic radiotherapy. SCRT a more localized irradiation compared to conventional fractionated radiotherapy. The use of some long-term efficacy and although data on long-term tumour survival and late are also As with SCRT should also be used with and in long-term This was by the of The The also from and The a of from the the are of the and not of the are to of for in the of the