Clinical Endocrinology (2000) 52, 695±702
Stereotactic conformal radiotherapy for pituitary adenomas: technique and preliminary experience R. Jalali*, M. Brada*², J. R. Perks³, A. P. Warrington³, D. Traish*, L. Burchell*, H. McNair§, D. G. T. Thomas¶, S. Robinson** and D. G. Johnston** *Neuro-Oncology Unit and ²Academic Unit of Radiotherapy and Oncology, Departments of ³Physics and §Radiotherapy, The Institute of Cancer Research and The Royal Marsden NHS Trust; ¶Department of Neurosurgery, The National Hospital for Neurology and Neurosurgery; **Unit of Metabolic Medicine, St. Mary's Hospital, London, UK
Summary OBJECTIVE Stereotactic
conformal radiotherapy (SCRT) is a high precision technique of fractionated radiotherapy which ensures accurate delivery of radiation with reduction in the volume of normal tissue irradiated as compared to conventional external beam radiotherapy. We describe the technique and preliminary experience of SCRT in patients with residual and recurrent pituitary adenomas. PATIENTS AND METHODS Between February 1995 and March 1999, 22 patients (mean age: 45´3, range: 20±67 years) with residual or recurrent pituitary adenomas (13 nonfunctioning, nine secretory) were treated with SCRT. All were immobilized in a relocatable Gill±Thomas±Cosman (GTC) frame and tumour was localized on a postcontrast planning computerized tomography (CT) and MRI scan. The gross tumour volume (GTV) and the critical structures were outlined on contiguous 2±3 mm separated slices. A margin of 5 mm (12 patients) to 10 mm (10 patients) was grown around GTV in three-dimensions (3-D) to generate the planning target volume (PTV). The treatment was delivered by three (®ve patients) and four (17 patients) maximally separated conformal ®xed ®elds with each ®eld conformed to the shape of the tumour using customized lead alloy blocks (19 patients) or multileaf collimator (three patients). The patients were treated on a 6-MV linear accelerator to a dose of 45 Gy in 25 Correspondence: Michael Brada, Neuro-oncology Unit, The Institute of Cancer Research and The Royal Marsden NHS Trust, Downs Road, Sutton, Surrey, SM2 5PT, UK. Fax: 44 (0)181 643 5469; E-mail: [email protected] q 2000 Blackwell Science Ltd
fractions (18 patients) and 50 Gy in 30 fractions (four patients). RESULTS The technique of SCRT has become a part of the routine work of the radiotherapy department. The treatment was well tolerated with minimal acute toxicity. One patient developed transient quadrantanopia 2 weeks after treatment with full recovery after a short course of corticosteroids. One patient had a transient visual deterioration 7 months after treatment due to cystic degeneration of the tumour which fully recovered following surgical decompression. Nine of the 15 patients presenting with visual impairment had improvement after treatment and the visual status remained stable in all others. One patient with acromegaly and one with a prolactinoma achieved normalization of elevated hormonal abnormality four and 10 months after SCRT, respectively. The remaining seven patients with a secretory adenoma had declining hormone levels at last follow-up. Newly initiated hormone replacement therapy was required in ®ve patients. At a median follow-up of 9 months (range 1±44 months), the 1 and 2 year actuarial progression free and overall survival were 100%. CONCLUSION Stereotactic conformal radiotherapy is a high precision technique suitable for the treatment of pituitary adenomas requiring radiotherapy. Preliminary results suggest effective tumour control and low toxicity within the range expected for conventional external beam radiotherapy. While the technique is of potential bene®t in reducing the volume of normal brain irradiated, the advantages in terms of sustained tumour control and reduced toxicity over conventional radiotherapy need to be demonstrated in long-term prospective studies. Surgery as the initial treatment for secretory and nonfunctioning pituitary adenomas is effective in relieving the pressure effect of the pituitary mass and in reducing elevated hormone levels (Bloom, 1973; Davis et al., 1993; Ebersold et al., 1986; Schuster et al., 1981). However, even with improved surgical techniques, a proportion of patients remain with residual tumour which may progress and patients with secretory adenomas may continue to have elevated hormone levels (Ciric et al., 1983; Comtois et al., 1991; Parl et al., 1986). Conventional fractionated external beam radiotherapy is frequently administered to patients with residual and recurrent 695
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disease and achieves long-term control in both secretory and nonfunctioning tumours (Brada et al., 1993; Breen et al., 1998; Grigsby et al., 1989; Tsang et al., 1994, 1996; McCollough et al., 1991; Rush & Cooper, 1997). Radiation is usually delivered to the tumour and the entire pituitary fossa with a 1±2 cm margin by a three-®eld technique of two opposing lateral ®elds and one anterior oblique ®eld lying in the same plane. The arrangement of the radiation ®elds leads to areas of relatively high dose regions in the frontal and temporal lobes. Stereotactic radiosurgery (SRS) using either a multiheaded cobalt unit (gamma knife) or a modi®ed linear accelerator is a high precision technique which delivers small localized spheres of irradiation with a steep dose gradient between high and low dose regions. Single fraction SRS has been considered a potential alternative to either surgery or conventional radiotherapy in the treatment of localized benign tumours such as pituitary adenomas. Because of the damaging effects of high single doses of radiation to normal CNS structures (Tishler et al., 1993; Marks, 1994; Leber et al., 1998), SRS is only suitable for small intrasellar tumours 0´5±1 cm away from the optic apparatus. The majority of pituitary tumours considered for radiotherapy are relatively large, nonspherical and in close proximity to the optic apparatus and therefore not suitable for safe SRS. The optimum way of delivering localized irradiation to nonspherical tumours with linear accelerator stereotactic radiation is by multiple conformal ®xed ®elds with individualized shielding of each radiation ®eld conforming to the shape of the tumour (Laing et al., 1993a; Alheit et al., 1999). This principle of conformal therapy combined with the high precision of stereotactic localization and focused radiation delivery is described as stereotactic conformal radiotherapy (SCRT). An arrangement of 4±6 noncoplanar ®elds provides a practical technique for the treatment of sellar and parasellar tumours with optimum sparing of normal brain (Perks et al., 1999). SCRT with relocatable methods of immobilization also allows for conventional fractionation which is known to be associated with lower morbidity to the normal nervous tissue than single fraction high doses of radiation. We report the technique of SCRT, its optimization, clinical application and preliminary results in patients with pituitary adenomas. Patients and methods Between February 1995 and March 1999, 25 patients with residual or recurrent pituitary adenoma were treated with fractionated stereotactic conformal radiotherapy (SCRT) at the Royal Marsden NHS Trust. Three patients received SCRT for a recurrent pituitary adenoma after previous radiotherapy and have been excluded from the present analysis. The patient and disease characteristics of the 22 patients are shown in Table 1. Fifteen patients received SCRT for residual tumour after
Table 1 Patient and disease characteristics of 22 pateints with pituitary adenoma treated with SCRT Variables Age (years) Mean Range Gender Male Female Initial secretory status Non-functioning Acromegaly (growth hormone) Prolactinomas Tumour extension* Suprasellar Cavernous sinus Sphenoid sinus 3rd ventricle and temporal lobe Timing of SCRT Residual disease after 1st surgery Residual disease after 2nd surgery Recurrence after 1st surgery Recurrence after surgery and medical treatment
No. of patients 45´3 20±67 14 8 13 5 4 16 12 6 1 13 2 3 4
*Tumour extends in more than one direction in some patients
incomplete excision, four following progression after surgery and medical therapy and three for recurrent tumour after surgery alone. Thirteen patients had a nonfunctioning adenoma and nine had a secreting tumour (®ve acromegaly and four prolactinoma). Two patients with prolactinoma had failed previous bromocriptine and two patients with acromegaly failed somatostatin analogues. Fourteen patients were male and eight female and were aged 20±67 years (mean 45 years). Patients had large tumours with extension into the suprasellar region (16), cavernous sinus (12), sphenoid sinus (six) and temporal lobe and third ventricle (one). SCRT technique The treatment apparatus, immobilization procedure, patient alignment and quality assurance have been reported previously (Laing et al., 1993; Graham et al., 1991b; Warrington et al., 1994). Patients were immobilized in the relocatable stereotactic Gill±Thomas±Cosman (GTC) frame (Gill et al., 1991; Graham et al., 1991a). All underwent a contrast enhanced CT scan at 2± 3 mm interval in the tumour bearing area and 4±6 mm outside. A Cosman±Roberts±Wells (Radionics Inc., Burlington, MA, USA) ®ducial system was used for stereotactic space de®nition (Kooy et al., 1994). The gross tumour volume (GTV) de®ned as visible tumour mass and any area presumed to contain tumour was manually contoured on sequential CT slices. Where q 2000 Blackwell Science Ltd, Clinical Endocrinology, 52, 695±702
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Fig. 1 Diagrammatic 3-D view of a standard four-®eld SCRT treatment plan with conformal blocking.
de®nition of tumour was dif®cult by CT a fused image of CT and magnetic resonance imaging (MRI) scan was used (Alexander et al., 1995). The planning target volume (PTV) was de®ned as GTV plus a margin grown in three-dimensions (3D). The margin for PTV was initially set at a conservative 10 mm. With greater experience and con®dence in imaging and accuracy of the SCRT technique, the margin was reduced to 5 mm. Critical structures including the eyes, optic nerves, optic chiasm and hypothalamus were also outlined. As the doses prescribed were well within the known tolerance of the optic apparatus, no modi®cation of PTV was done to avoid the optic chiasm/nerves. Treatment planning was carried out using a dedicated software program (Cadplan or GE Target Prism Microsystems Ltd., Borehamwood, UK) according to standard guidelines with respect to target coverage and dose homogeneity within the PTV (ICRU 50., 1993). Optimization studies of sellar and parasellar tumours suggested that four noncoplanar ®xed conformal ®elds achieved optimum sparing of the normal q 2000 Blackwell Science Ltd, Clinical Endocrinology, 52, 695±702
Table 2 SCRT treatment parameters of 22 patients with pituitary adenoma Gross tumour volume (GTV) Mean Range Planning target volume (PTV) Mean Range Conformation of PTV Customized blocks Multileaf collimator Dose prescription 45 Gy/25#/5 weeks 50 Gy/30#/6 weeks Field arrangement Three-®eld technique Four-®eld technique
26´83 cm3 2´7±77 cm3 45´05 cm3 13´72±112´78 cm3 19 3 18 4 5 17
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brain and became the standard treatment technique for SCRT of pituitary adenomas (Perks et al., 1999) (Fig. 1). The ®elds were individually shaped to conform to the shape of the target volume using either customized lead alloy blocks (19 patients) or a multileaf collimator (three patients). The dose algorithms employed by the planning systems are Bentley±Milan and pencil beam for Target II and Cadplan, respectively, with both algorithms accounting for in-®eld blocking through an equivalent square calculation. The treatment parameters are summarized in Table 2. To assess the accuracy of relocation, the isocentre position was veri®ed with a second CT scan in the frame taken just prior to the start of treatment. The tolerance of relocation had to be < 1´5 mm in any direction. Dose prescription Doses were prescribed at the isocentre according to the ICRU 50 criteria with PTV covered by the 95% isodose in 3-D. A uniform dose homogeneity was ensured within the PTV with rapid dose fall off outside and minimal dose to the surrounding normal brain. Eighteen patients received 45Gy in 25 fractions and four patients 50 Gy in 30 fractions treating for 5 days a week. The treatment was delivered on a 6-MV linear accelerator (Varian 600C/2100C Varian Medical Systems, Palo Alto, CA, USA). Data analysis Patients were seen weekly during the course of radiotherapy and 1 month after the completion of treatment. Subsequent follow-up was in an endocrine clinic with regular hormone pro®le assessment. Tumour control was de®ned by the absence of clinical and radiological progression and stable or decreasing hormone levels in secreting adenomas. The effect of therapy on Table 3 Endocrine assessment in secretory tumours No. of patients Acromegaly³ Normalized GH and IGF-1* Declining levels** GH > 104 mU/l remaining high Prolactinomas³ Normalized prolactin² Declining levels*** Lost to follow-up
6 1 4 1 4 1 2 1
*GH < 2 mU/l during oral glucose tolerance test and IGF 1 < 50 nmol/L; ² Prolactin < 480 mU/L; ³ includes mixed GH & PRL secreting; **GH levels 31´6 (r) 1´9 (2 months), 19 (r) 7 (4 months), 45±20 (4 months), 103 (r) 13´3 (5 months); 15´3 (r) 9´7 (5 months) [mU/l (month)]; ***PRL levels 5000 (r) 3´480 (12/12), 1288 (r) 657 (14/12) [mU/l (months)].
Table 4 Visual status of 22 patients with pituitary adenoma after SCRT Vision at presentation (number of patients)
Improvement
Unchanged
Deterioration
± 1 2
7 ± 2
± ± ±
6
4
2*
Normal vision (7) Impaired visual acuity (1) Visual ®eld defect (4) Impaired acuity and ®eld defect (10)
*Transient.
vision was assessed on serial ophthalmological examinations. Survival and progression-free survival were measured from the start of SCRT.
Results Local control and survival Twenty-two patients with residual and recurrent pituitary adenoma were treated with SCRT. The median follow-up was 9 months (range 1±44 months). Follow-up MRI imaging was available in 13 patients 1±26 months after treatment. There was a reduction in the size of the tumour in ®ve patients and no change in others. The 1 and 2 year actuarial progression free and overall survival are 100%. Effect of therapy in secretory tumours Endocrine assessment in patients with secretory adenomas is summarized in Table 3. Six patients had declining values of initially elevated hormones. One patient with mixed GH secreting tumour and prolactinoma had normalization of elevated GH with unchanged prolactin. One patient with GH > 104 mU/l remained with high level six months after treatment, and one patient was lost to follow-up (returned abroad). None of the patients with normalized or reducing hormone level had a subsequent rise. Effect of therapy on vision Fifteen patients had impaired vision prior to SCRT (Table 4). Improvement of vision after treatment was seen in nine patients. One patient had a mild transient deterioration in vision in the form of quadrantanopia two weeks after treatment and received a short course of corticosteroids with full recovery of vision. One patient had a visual deterioration seven months after treatment and an MRI revealed cystic degeneration of the residual pituitary mass impinging on the optic chiasm. Following cyst drainage, there was full recovery of vision q 2000 Blackwell Science Ltd, Clinical Endocrinology, 52, 695±702
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Table 5 Pituitary function of 22 patients with pituitary adenoma after SCRT Hypopituitarism Steroid axis Gonadal axis Thyroid Vasopressin
Pre-SCRT
Post-SCRT*
12 10 6 1
2/10 3/12 3/16 0/21
*Number of patients requiring replacement/number at risk.
which remains normal at the time of last follow up. Vision remained stable in all other patients. Adverse effects Most patients developed temporary localized alopecia at the beam entrance. Five patients developed mild transient postradiotherapy somnolence which recovered within 8 weeks of completion of treatment. Prospective assessment of cognitive function was not performed but none of the patients developed obvious memory impairment or neuropsychological dysfunction. No patient developed late visual de®cit attributable to radiotherapy. Endocrine function Six patients had panhypopituitarism at the time of SCRT and were on hormone replacement therapy. Of six patients with normal pituitary function prior to radiotherapy, two developed endocrine de®ciency at 5 and 6 months after SCRT requiring hormone replacement (one hydrocortisone, one hydrocortisone and testosterone). Two patients with steroid axis de®ciency alone at the time of SCRT required additional replacement with thyroxine and testosterone at 2 and 15 months, respectively, after treatment. One patient on oestrogen replacement required thyroxine 6 months after treatment (Table 5). Discussion There is considerable debate about the role of radiotherapy in the management of patients with pituitary adenoma. Nevertheless, radiotherapy is frequently used in patients with residual or recurrent tumours. Conventional fractionated external beam radiotherapy to doses of 45±55 Gy given over a period of 5± 6 weeks achieves long-term tumour control ranging from 80 to 97% at 10 years and 72±92% at 20 years (Urdaneta et al., 1976; Erlichman et al., 1979; Brada et al., 1993; McCollough et al., 1991; Grigsby et al., 1988; Breen et al., 1998; Tsang et al., 1996; Gittoes et al., 1998). Modern radiotherapy techniques deliver more precise and localized radiation than conventional radiotherapy with a q 2000 Blackwell Science Ltd, Clinical Endocrinology, 52, 695±702
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steeper dose gradient between high and low dose regions. Stereotactic radiosurgery/radiotherapy techniques involve ®rm and accurate immobilization with ®xed or relocatable frames, high precision 3-D target localization with CT/CT-MRI fusion and focused radiation delivery. This is achieved either with a multiheaded cobalt unit (gamma knife) or with multiple arcs using a modi®ed conventional linear accelerator. Such conventional stereotactic irradiation techniques typically produce spherical high dose volumes and are therefore suitable only for small spherical lesions (Graham et al., 1991b). A majority of pituitary adenomas considered for radiotherapy are not spherical and frequently extend to adjacent structures including the cavernous sinus, optic chiasm and sphenoid sinus. To treat large nonspherical volumes with conventional SRS requires the addition of multiple small spherical high dose volumes described as multiple isocentre treatment. The overlap of high dose spheres results in dose inhomogeneity which has been associated with a higher incidence of radiation induced complications (Nedzi et al., 1991). We have previously demonstrated that the optimum way of delivering high precision localized irradiation to larger nonspherical targets is with the use of multiple conformal ®xed ®elds with individualized shielding of each radiation ®eld conforming to the shape of the target (Laing et al., 1993a). This principle of conformal therapy combined with the precision of stereotactic localization and focused radiation delivery is described as stereotactic conformal radiotherapy. Traditionally stereotactic irradiation has been delivered in a single session as single fraction radiosurgery. High doses of radiation given in one fraction are known to be associated with a high risk of radiation induced damage to normal tissue and this is particularly true for the central nervous system (Sheline et al., 1980). Giving radiation in small individual doses allows the delivery of higher radiation doses without serious injury to the normal tissues which is especially important for normal CNS structures (Marks et al., 1981). Single fraction SRS is associated with considerable neurological toxicity to the optic apparatus (Tishler et al., 1993) (Leber et al., 1998) the cranial nerves (Leber et al., 1998; Engenhart et al., 1990) and normal brain (Mitsumori et al., 1998). With the advent of high precision relocatable noninvasive means of immobilization, it has become possible to deliver stereotactic irradiation in a fractionated manner (Laing et al., 1993b). The technique of SCRT combines the precision of focused radiation delivery and the radiobiological advantages of fractionation. It also ensures homogenous dose distribution within the irradiated volume further reducing the risk of damage. The aim of high precision SCRT is to achieve a high dose differential between the tumour and the surrounding normal tissues. This allows for either an increase in the tumour dose to improve local control or for a potential decrease in radiation damage to the normal tissues. As there is no clear bene®t in
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tumour control of pituitary adenomas with doses beyond 45±50 Gy (McCollough et al., 1991; McCord et al., 1997; Breen et al., 1998), the aim of SCRT is to achieve high tumour control rates seen with conventional radiotherapy while minimizing the risk of CNS injury from radiation. SCRT was therefore given to 45± 50 Gy in 25±30 daily fractions over a period of 5±6 weeks (®ve fractions per week) delivered at a standard dose per fraction of 1´67±1´8 Gy. Tumour control at relatively short follow-up is excellent within the range reported following conventional external beam radiotherapy. Longer follow-up is required to have full con®dence that the excellent early tumour control is retained. It has been suggested that in patients with secretory tumours single fraction SRS compared to fractionated radiotherapy produces a more rapid normalization of elevated hormone levels (Landolt et al., 1998; Yoon et al., 1998). The current reports of SRS are based on retrospective comparison with a cohort of patients treated with fractionated radiotherapy with ¯aws in the pretreatment matching of the hormone levels between the two treatment modalities and no information about the rate of decline of individual hormone levels (Jalali & Brada, 1999). While SRS may produce a faster decline in elevated hormone levels than fractionated radiotherapy, the evidence so far does not support the hypothesis and remains to be proven in prospective trials. The rate of normalization of the elevated hormone levels following SCRT is as would be expected following conventional fractionated radiotherapy with no increase in hormone levels. The follow-up is however, too short to be certain about long-term ef®cacy. The most commonly reported late morbidity of conventional radiotherapy is hypopituitarism with cumulative actuarial risk of 20±50% at 10±20 years (Shalet, 1981; Brada et al., 1993; Tsang et al., 1994). Hypopituitarism is likely to be due to the damage to both hypothalamus and pituitary, although the former is considered of primary importance (Samaan et al., 1975). Stereotactic irradiation techniques aim to reduce radiation dose to adjacent normal tissue. It has been suggested that this may lead to more effective preservation of normal pituitary function. The reported incidence of pituitary endocrine failure following SRS (Yoon et al., 1998; Mitsumori et al., 1998) is high within the range expected following conventional radiotherapy and this is also the case for SCRT. Despite the more localized nature of irradiation with SRS and SCRT, the doses of irradiation actually delivered to the hypothalamus are considerable. Further optimization studies are needed to develop techniques which minimize radiation doses to the hypothalamus. However damage to the pituitary gland may also contribute and none of the treatment techniques so far can avoid irradiating the residual glandular tissue in patients with macroadenomas. In the treatment of large nonspherical tumours, the optic apparatus is commonly included in the high dose volume of irradiation. Single fraction SRS to the optic pathways has been
associated with a high risk of damage (Tishler et al., 1993; Witt et al., 1996). The frequency of damage is dose dependent with 78% risk of optic neuropathy in patients receiving > 15 Gy and 27% risk for those receiving 10±15 Gy to the optic apparatus (Leber et al., 1998). The incidence of radiation induced visual impairment following conventional fractionated radiotherapy doses of 45±50 Gy in 25±30 fractions delivered at standard fractionation schedule over 5±6 weeks is 1±3% (Brada et al., 1993; McCord et al., 1997; Tsang et al., 1994). The lack of visual damage attributable to SCRT is therefore within the expected range for this small group of patients at a short follow-up. External beam irradiation is associated with the development of second radiation induced neoplasms with reported cumulative actuarial risk in patients with pituitary adenoma of 2±2´7% at 10±30 years (Brada et al., 1992; Breen et al., 1998; Tsang et al., 1993) not seen in all studies (Jones, 1991; Bliss et al., 1994). Localized radiotherapy techniques of SRS and SCRT may reduce the incidence of second tumours but are unlikely to eliminate it. To demonstrate a small reduction will require a very large number of patients and a long follow-up. Radionecrosis is a recognized complication of CNS radiotherapy usually to doses beyond conventional radiation tolerance (Aristizabel et al., 1977; Fontana et al., 1984; Fukamachi et al., 1982; Lampert et al., 1964). The term `radionecrosis' has been used inconsistently ranging from mild asymptomatic white matter parenchymal changes to frank pathologically proven necrotic masses (al Mefty et al., 1990) (Diengdoh et al., 1976) (Eyster et al., 1974) (Peck et al., 1966). The risk of radiation necrosis increases with dose, dose per fraction and volume of normal brain irradiated (Kramer, 1968) (Marks et al., 1981, 1985). Delayed brain parenchymal injury including radionecrosis following irradiation of pituitary tumours has been reported in lateral temporal lobes and is attributed to high dose regions using parallel opposed ®elds and the use of orthovoltage radiotherapy (al Mefty et al., 1990; Fontana et al., 1984). The incidence of radionecrosis with the use of modern technology with high energy megavoltage linear accelerators at standard dose-fractionation (< 50 Gy at < 2 Gy/ fraction) is extremely low (Sheline et al., 1980; Marks et al., 1981). Although SRS delivers localized irradiation to small volumes the single fraction doses are relatively large and have been associated with radionecrosis in temporal lobe in three out of 12 patients (28% actuarial risk at 3 years) (Mitsumori et al., 1998). There have been no cases of radionecrosis seen in patients treated with fractionated stereotactic radiotherapy (Mitsumori et al., 1998) and in the present study. High dose irradiation volumes in the temporal and frontal lobes with conventional radiotherapy techniques has been also widely believed to cause late neurocognitive dysfunction. Although formal cognitive function studies have failed to detect a de®nite impairment due to irradiation alone (Grattan Smith et al., q 2000 Blackwell Science Ltd, Clinical Endocrinology, 52, 695±702
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1992; Peace et al., 1997), a mild radiation induced de®cit cannot be ruled out without a full prospective study (McCord et al., 1997). Minimizing the radiation dose to the normal brain tissue through SCRT has the potential of reducing the putative risk of cognitive impairment. No patient in the current study has developed a new neurocognitive abnormality so far although this was not formally tested. We conclude that stereotactic conformal radiotherapy is a practical and relatively easily applicable high precision localized irradiation treatment technique which can be incorporated in the daily routine of a busy radiotherapy department. The technique is suitable for the treatment of pituitary adenomas requiring radiotherapy. Early results in terms of local control and toxicity are comparable to conventional radiotherapy and longer follow-up is required to assess its true effectiveness in terms of sustained tumour control and reduction in treatment related toxicity. Acknowledgements The work was supported in part by the Neuro-Oncology Research fund, The Royal Marsden NHS Trust and the Cancer Research Campaign. We are grateful to our neurosurgical and endocrinology colleagues for their continued collaboration. This work was undertaken by the Royal Marsden NHS Trust who received a proportion of its funding from the NHS executive; the views expressed are those of the authors and not necessarily those of the NHS executive. References al Mefty, O., Kersh, J.E., Routh, A. & Smith, R.R. (1990) The long-term side effects of radiation therapy for benign brain tumors in adults. Journal of Neurosurgery, 73, 502±512. Alexander, E., 3rd, Kooy., H.M., van Herk, M., Schwartz, M., Barnes, P.D., Tarbell, N., Mulkern, R.V., Holupka, E.J. & Loef¯er, J.S. (1995) Magnetic resonance image-directed stereotactic neurosurgery: use of image fusion with computerized tomography to enhance spatial accuracy. Journal of Neurosurgery, 83, 271±276. Alheit, H., Saran, F.H., Warrington, A.P., Rosenberg, I., Perks, J., Jalali, R., Shepherd, S., Beardmore, C., Baumert, B. & Brada, M. (1999) Stereotactically guided conformal radiotherapy for meningiomas. Radiotherapy and Oncology, 50, 145±150. Aristizabel, S., Caldwell, W.L. & Avila, J. (1977) The relationship of time dose fractionalism factors to complications in the treatment of pituitary tumours by irradiation. International Journal of Radiation, Encology, Biology and Physics, 2, 667±673. Bliss, P., Kerr, G.R. & Gregor, A. (1994) Incidence of second brain tumours after pituitary irradiation in Edinburgh 1962±90. Clinical Oncological Royal College of Radiology, 6, 361±363. Bloom, H.J.G. (1973) Radiotherapy of pituitary tumours. In: Pituitary Tumours, (Jenkins, J.S., ed.) pp. 186±189. Butterworths, London. Brada, M., Ford, D., Ashley, S., Bliss, J.M., Crowley, S., Mason, M., Rajan, B. & Traish, D. (1992) Risk of second brain tumour after conservative surgery and radiotherapy for pituitary adenoma. British Medical Journal, 304, 1343±1346. q 2000 Blackwell Science Ltd, Clinical Endocrinology, 52, 695±702
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ICRU (1993) Report 50 Prescribing, recording and reporting photon beam therapy International commission on radiation units and measurements. Jalali, R. & Brada, M. (1999) Radiosurgery for pituitary adenomas. Critical Reviews In Neurosurgery, 9, 167±173. Jones, A. (1991) Radiation oncogenesis in relation to the treatment of pituitary tumours. Clinical Endocrinology, 35, 379±397. Kooy, H.M., Dunbar, S.F., Tarbell, N.J., Mannarino, E., Ferarro, N., Shusterman, S., Bellerive, M., Finn, L., McDonough, C.V. & Loef¯er, J.S. (1994) Adaptation and veri®cation of the relocatable Gill Thomas Cosman frame in stereotactic radiotherapy. International Journal of Radiation Oncology, Biology and Physics, 30, 685±691. Kramer, S. (1968) The value of radiation therapy for pituitary and parapituitary tumours. Canadian Medical Association Journal, 99, 1120±1127. Laing, R.W., Bentley, R.E., Nahum, A.E., Warrington, A.P. & Brada, M. (1993a) Stereotactic radiotherapy of irregular targets: a comparison between static conformal beams and non coplanar arcs. Radiotherapy and Oncology, 28, 241±246. Laing, R.W., Thompson, V., Warrington, A.P. & Brada, M. (1993b) Feasibility of patient immobilization for conventional cranial irradiation with a relocatable stereotactic frame. British Journal of Radiology, 66, 1020±1024. Lampert, P.W. & Davis, R.L. (1964) Delayed effects of radiation on the human central nervous system. ``Early'' and ``late'' delayed reactions. Neurology, 14, 912±917. Landolt, A.M., Haller, D., Lomax, N., Scheib, S., Schubiger, O., Siegfried, J. & Wellis, G. (1998) Stereotactic radiosurgery for recurrent surgically treated acromegaly: comparison with fractionated radiotherapy. Journal of Neurosurgery, 88, 1002±1008. Leber, K.A., Bergloff, J. & Pendl, G. (1998) Dose±response tolerance of the visual pathways and cranial nerves of the cavernous sinus to stereotactic radiosurgery. Journal of Neurosurgery, 88, 43±50. Marks, L.B. (1994) Complications following radiosurgery: a review. Radiation and Oncology Investigations, 2, 1±11. Marks, J.E., Baglan, R.J., Prassad, S.C. & Blank, W.F. (1981) Cerebral radionecrosis: incidence and risk in relation to dose, time, fractionation and Volume. International Journal of Radiation Oncology, Biology and Physics, 7, 243±252. Marks, J.E. & Wong, J. (1985) The risk of cerebral radionecrosis in relation to dose, time and fractionation. A follow-up study. Progress in Experimental Tumor Research, 29, 210±218. McCollough, W., Marcus, R.J., Rhoton, A., Ballinger, W. & Million, R. (1991) Long term follow up of radiotherapy for pituitary adenoma: The absence of late recurrence after 4500cGy. International Journal of Radiation Oncology, Biology and Physics, 21, 607±614. McCord, M.W., Buatti, J.M., Fennell, E.M., Mendenhall, W.M., Marcus, R.B.J., Rhoton, A.L., Grant, M.B. & Friedman, W.A. (1997) Radiotherapy for pituitary adenoma: long-term outcome and sequelae. International Journal of Radiation Oncology, Biology and Physics, 39, 437±444. Mitsumori, M., Shrieve, D., Alexander, E., Kaiser, U., Richardson, G., Black, P. & Loef¯er, J. (1998) Initial clinical results of LINAC-based stereotactic radiosurgery and stereotactic radiotherapy for pituitary adenomas. International Journal of Radiation Oncology, Biology and Physics, 42, 573±580. Nedzi, L., Kooy, H., Alexander, E., Gelman, R. & Loef¯er, J. (1991) Variables associated with the development of complications from radiosurgery of intracranial tumours. International Journal of Radiation Oncology, Biology and Physics, 21, 591±599. Parl, F.F., Cruz, V.E., Cobb, C.A., Bradley, C.A. & Aleshire, S.L.
(1986) Late recurrence of surgically removed prolactinomas. Cancer, 57, 2422±2426. Peace, K.A., Orme, S.M., Sebastian, J.P., Thompson, A.R., Barnes, S., Ellis, A. & Belchetz, P.E. (1997) The effect of treatment variables on mood and social adjustment in adult patients with pituitary disease. Clinical Endocrinology, 46, 445±450. Peck, F.C. Jr. & McGovern, E.R. (1966) Radiation necrosis of the brain in acromegaly. Journal of Neurosurgery, 25, 536±542. Perks, J.R., Jalali, R., Cosgrove, V., Adams, E.J., Shepherd, S.F., Warrington, A.P. & Brada, M. (1999) Optimization of stereotactically guided conformal treatment planning of sellar and parasellar tumours; based on normal brain dose Volume histograms. International Journal of Radiation Oncology, Biology and Physics, 45, 507±513. Rush, S. & Cooper, P.R. (1997) Symptom resolution, tumor control, and side effects following postoperative radiotherapy for pituitary macroadenomas. International Journal of Radiation Oncology, Biology and Physics, 37, 1031±1034. Samaan, N.A., Bakdash, M.M., Caderao, J.B., Cangir, A., Jesse, R.H. Jr & Ballantyne, A.J. (1975) Hypopituitarism after external irradiation. Evidence for both hypothalamic and pituitary origin. Annals of Internal Medicine, 83, 771±777. Schuster, L.D., Bantle, J.P., Oppenheimer, J.H. & Seljeskog, E.L. (1981) Acromegaly: reassessment of the long-term therapeutic effectiveness of transsphenoidal pituitary surgery. Annals of Internal Medicine, 95, 172±174. Shalet, S.M. (1981) Iatrogenic hypothalamic pituitary disease. In: Clinical Endocrinology 1: the Pituitary, (Beardwell, C. & Robertson, G.L., eds.) pp. 175±210. Butterworths, London. Sheline, G.E., Wara, W.M. & Smith, V. (1980) Therapeutic irradiation and brain injury. International Journal of Radiation Oncology, Biology and Physics, 6, 1215±1228. Tishler, R.B., Loef¯er, J.S., Lunsford, D., Duma, C., Alexander, E.I.I.I., Kooy, H.M. & Flickinger, J.C. (1993) Tolerance of cranial nerves of the cavernous sinus to radiosurgery. International Journal of Radiation Oncology, Biology and Physics, 27, 215±221. Tsang, R., Laperriere, N., Simpson, W., Brierley, J., Panzarella, T. & Smyth, H. (1993) Glioma arising after radiation therapy for pituitary adenoma: a report of four patients and estimation of risk. Cancer, 72, 2227±2233. Tsang, R.W., Brierley, J.D., Panzarella, T., Gospodarowicz, M.K., Sutcliffe, S.B. & Simpson, W.J. (1994) Radiation therapy for pituitary adenoma: treatment outcome and prognostic factors. International Journal of Radiation Oncology, Biology and Physics, 30, 557±565. Tsang, R.W., Brierley, J.D., Panzarella, T., Gospodarowicz, M.K., Sutcliffe, S.B. & Simpson, W.J. (1996) Role of radiation therapy in clinical hormonally-active pituitary adenomas. Radiotherapy and Oncology, 41, 45±53. Urdaneta, N., Chessin, H. & Fischer, J. (1976) Pituitary adenomas and craniopharyngiomas: analysis of 99 cases treated with radiation therapy. International Journal of Radiation Oncology, Biology and Physics, 1, 895±902. Warrington, A.P., Laing, R.W. & Brada, M. (1994) Quality assurance in fractionated stereotactic radiotherapy. Radiotherapy and Oncology, 30, 239±246. Witt, C.W., Kondziolka, D., Flickinger, J.C. & Lunsford, L.D. (1996) Stereotactic radiosurgery for pituitary tumours. In: Radiosurgery 1995, (D.K., eds.) pp. 55±65. Karger, Basel. Yoon, S.C., Suh, T.S., Jang, H.S., Chung, S.M., Kim, Y.S., Ryu, M.R., Choi, K.H., Son, H.Y., Kim, M.C. & Shinn, K.S. (1998) Clinical results of 24 pituitary macroadenomas with linac-based stereotactic radiosurgery. International Journal of Radiation Oncology, Biology and Physics, 41, 849±853. q 2000 Blackwell Science Ltd, Clinical Endocrinology, 52, 695±702
Stereotactic conformal radiotherapy for pituitary adenomas: technique and preliminary experience R. Jalali*, M. Brada*², J. R. Perks³, A. P. Warrington³, D. Traish*, L. Burchell*, H. McNair§, D. G. T. Thomas¶, S. Robinson** and D. G. Johnston** *Neuro-Oncology Unit and ²Academic Unit of Radiotherapy and Oncology, Departments of ³Physics and §Radiotherapy, The Institute of Cancer Research and The Royal Marsden NHS Trust; ¶Department of Neurosurgery, The National Hospital for Neurology and Neurosurgery; **Unit of Metabolic Medicine, St. Mary's Hospital, London, UK
Summary OBJECTIVE Stereotactic
conformal radiotherapy (SCRT) is a high precision technique of fractionated radiotherapy which ensures accurate delivery of radiation with reduction in the volume of normal tissue irradiated as compared to conventional external beam radiotherapy. We describe the technique and preliminary experience of SCRT in patients with residual and recurrent pituitary adenomas. PATIENTS AND METHODS Between February 1995 and March 1999, 22 patients (mean age: 45´3, range: 20±67 years) with residual or recurrent pituitary adenomas (13 nonfunctioning, nine secretory) were treated with SCRT. All were immobilized in a relocatable Gill±Thomas±Cosman (GTC) frame and tumour was localized on a postcontrast planning computerized tomography (CT) and MRI scan. The gross tumour volume (GTV) and the critical structures were outlined on contiguous 2±3 mm separated slices. A margin of 5 mm (12 patients) to 10 mm (10 patients) was grown around GTV in three-dimensions (3-D) to generate the planning target volume (PTV). The treatment was delivered by three (®ve patients) and four (17 patients) maximally separated conformal ®xed ®elds with each ®eld conformed to the shape of the tumour using customized lead alloy blocks (19 patients) or multileaf collimator (three patients). The patients were treated on a 6-MV linear accelerator to a dose of 45 Gy in 25 Correspondence: Michael Brada, Neuro-oncology Unit, The Institute of Cancer Research and The Royal Marsden NHS Trust, Downs Road, Sutton, Surrey, SM2 5PT, UK. Fax: 44 (0)181 643 5469; E-mail: [email protected] q 2000 Blackwell Science Ltd
fractions (18 patients) and 50 Gy in 30 fractions (four patients). RESULTS The technique of SCRT has become a part of the routine work of the radiotherapy department. The treatment was well tolerated with minimal acute toxicity. One patient developed transient quadrantanopia 2 weeks after treatment with full recovery after a short course of corticosteroids. One patient had a transient visual deterioration 7 months after treatment due to cystic degeneration of the tumour which fully recovered following surgical decompression. Nine of the 15 patients presenting with visual impairment had improvement after treatment and the visual status remained stable in all others. One patient with acromegaly and one with a prolactinoma achieved normalization of elevated hormonal abnormality four and 10 months after SCRT, respectively. The remaining seven patients with a secretory adenoma had declining hormone levels at last follow-up. Newly initiated hormone replacement therapy was required in ®ve patients. At a median follow-up of 9 months (range 1±44 months), the 1 and 2 year actuarial progression free and overall survival were 100%. CONCLUSION Stereotactic conformal radiotherapy is a high precision technique suitable for the treatment of pituitary adenomas requiring radiotherapy. Preliminary results suggest effective tumour control and low toxicity within the range expected for conventional external beam radiotherapy. While the technique is of potential bene®t in reducing the volume of normal brain irradiated, the advantages in terms of sustained tumour control and reduced toxicity over conventional radiotherapy need to be demonstrated in long-term prospective studies. Surgery as the initial treatment for secretory and nonfunctioning pituitary adenomas is effective in relieving the pressure effect of the pituitary mass and in reducing elevated hormone levels (Bloom, 1973; Davis et al., 1993; Ebersold et al., 1986; Schuster et al., 1981). However, even with improved surgical techniques, a proportion of patients remain with residual tumour which may progress and patients with secretory adenomas may continue to have elevated hormone levels (Ciric et al., 1983; Comtois et al., 1991; Parl et al., 1986). Conventional fractionated external beam radiotherapy is frequently administered to patients with residual and recurrent 695
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disease and achieves long-term control in both secretory and nonfunctioning tumours (Brada et al., 1993; Breen et al., 1998; Grigsby et al., 1989; Tsang et al., 1994, 1996; McCollough et al., 1991; Rush & Cooper, 1997). Radiation is usually delivered to the tumour and the entire pituitary fossa with a 1±2 cm margin by a three-®eld technique of two opposing lateral ®elds and one anterior oblique ®eld lying in the same plane. The arrangement of the radiation ®elds leads to areas of relatively high dose regions in the frontal and temporal lobes. Stereotactic radiosurgery (SRS) using either a multiheaded cobalt unit (gamma knife) or a modi®ed linear accelerator is a high precision technique which delivers small localized spheres of irradiation with a steep dose gradient between high and low dose regions. Single fraction SRS has been considered a potential alternative to either surgery or conventional radiotherapy in the treatment of localized benign tumours such as pituitary adenomas. Because of the damaging effects of high single doses of radiation to normal CNS structures (Tishler et al., 1993; Marks, 1994; Leber et al., 1998), SRS is only suitable for small intrasellar tumours 0´5±1 cm away from the optic apparatus. The majority of pituitary tumours considered for radiotherapy are relatively large, nonspherical and in close proximity to the optic apparatus and therefore not suitable for safe SRS. The optimum way of delivering localized irradiation to nonspherical tumours with linear accelerator stereotactic radiation is by multiple conformal ®xed ®elds with individualized shielding of each radiation ®eld conforming to the shape of the tumour (Laing et al., 1993a; Alheit et al., 1999). This principle of conformal therapy combined with the high precision of stereotactic localization and focused radiation delivery is described as stereotactic conformal radiotherapy (SCRT). An arrangement of 4±6 noncoplanar ®elds provides a practical technique for the treatment of sellar and parasellar tumours with optimum sparing of normal brain (Perks et al., 1999). SCRT with relocatable methods of immobilization also allows for conventional fractionation which is known to be associated with lower morbidity to the normal nervous tissue than single fraction high doses of radiation. We report the technique of SCRT, its optimization, clinical application and preliminary results in patients with pituitary adenomas. Patients and methods Between February 1995 and March 1999, 25 patients with residual or recurrent pituitary adenoma were treated with fractionated stereotactic conformal radiotherapy (SCRT) at the Royal Marsden NHS Trust. Three patients received SCRT for a recurrent pituitary adenoma after previous radiotherapy and have been excluded from the present analysis. The patient and disease characteristics of the 22 patients are shown in Table 1. Fifteen patients received SCRT for residual tumour after
Table 1 Patient and disease characteristics of 22 pateints with pituitary adenoma treated with SCRT Variables Age (years) Mean Range Gender Male Female Initial secretory status Non-functioning Acromegaly (growth hormone) Prolactinomas Tumour extension* Suprasellar Cavernous sinus Sphenoid sinus 3rd ventricle and temporal lobe Timing of SCRT Residual disease after 1st surgery Residual disease after 2nd surgery Recurrence after 1st surgery Recurrence after surgery and medical treatment
No. of patients 45´3 20±67 14 8 13 5 4 16 12 6 1 13 2 3 4
*Tumour extends in more than one direction in some patients
incomplete excision, four following progression after surgery and medical therapy and three for recurrent tumour after surgery alone. Thirteen patients had a nonfunctioning adenoma and nine had a secreting tumour (®ve acromegaly and four prolactinoma). Two patients with prolactinoma had failed previous bromocriptine and two patients with acromegaly failed somatostatin analogues. Fourteen patients were male and eight female and were aged 20±67 years (mean 45 years). Patients had large tumours with extension into the suprasellar region (16), cavernous sinus (12), sphenoid sinus (six) and temporal lobe and third ventricle (one). SCRT technique The treatment apparatus, immobilization procedure, patient alignment and quality assurance have been reported previously (Laing et al., 1993; Graham et al., 1991b; Warrington et al., 1994). Patients were immobilized in the relocatable stereotactic Gill±Thomas±Cosman (GTC) frame (Gill et al., 1991; Graham et al., 1991a). All underwent a contrast enhanced CT scan at 2± 3 mm interval in the tumour bearing area and 4±6 mm outside. A Cosman±Roberts±Wells (Radionics Inc., Burlington, MA, USA) ®ducial system was used for stereotactic space de®nition (Kooy et al., 1994). The gross tumour volume (GTV) de®ned as visible tumour mass and any area presumed to contain tumour was manually contoured on sequential CT slices. Where q 2000 Blackwell Science Ltd, Clinical Endocrinology, 52, 695±702
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Fig. 1 Diagrammatic 3-D view of a standard four-®eld SCRT treatment plan with conformal blocking.
de®nition of tumour was dif®cult by CT a fused image of CT and magnetic resonance imaging (MRI) scan was used (Alexander et al., 1995). The planning target volume (PTV) was de®ned as GTV plus a margin grown in three-dimensions (3D). The margin for PTV was initially set at a conservative 10 mm. With greater experience and con®dence in imaging and accuracy of the SCRT technique, the margin was reduced to 5 mm. Critical structures including the eyes, optic nerves, optic chiasm and hypothalamus were also outlined. As the doses prescribed were well within the known tolerance of the optic apparatus, no modi®cation of PTV was done to avoid the optic chiasm/nerves. Treatment planning was carried out using a dedicated software program (Cadplan or GE Target Prism Microsystems Ltd., Borehamwood, UK) according to standard guidelines with respect to target coverage and dose homogeneity within the PTV (ICRU 50., 1993). Optimization studies of sellar and parasellar tumours suggested that four noncoplanar ®xed conformal ®elds achieved optimum sparing of the normal q 2000 Blackwell Science Ltd, Clinical Endocrinology, 52, 695±702
Table 2 SCRT treatment parameters of 22 patients with pituitary adenoma Gross tumour volume (GTV) Mean Range Planning target volume (PTV) Mean Range Conformation of PTV Customized blocks Multileaf collimator Dose prescription 45 Gy/25#/5 weeks 50 Gy/30#/6 weeks Field arrangement Three-®eld technique Four-®eld technique
26´83 cm3 2´7±77 cm3 45´05 cm3 13´72±112´78 cm3 19 3 18 4 5 17
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brain and became the standard treatment technique for SCRT of pituitary adenomas (Perks et al., 1999) (Fig. 1). The ®elds were individually shaped to conform to the shape of the target volume using either customized lead alloy blocks (19 patients) or a multileaf collimator (three patients). The dose algorithms employed by the planning systems are Bentley±Milan and pencil beam for Target II and Cadplan, respectively, with both algorithms accounting for in-®eld blocking through an equivalent square calculation. The treatment parameters are summarized in Table 2. To assess the accuracy of relocation, the isocentre position was veri®ed with a second CT scan in the frame taken just prior to the start of treatment. The tolerance of relocation had to be < 1´5 mm in any direction. Dose prescription Doses were prescribed at the isocentre according to the ICRU 50 criteria with PTV covered by the 95% isodose in 3-D. A uniform dose homogeneity was ensured within the PTV with rapid dose fall off outside and minimal dose to the surrounding normal brain. Eighteen patients received 45Gy in 25 fractions and four patients 50 Gy in 30 fractions treating for 5 days a week. The treatment was delivered on a 6-MV linear accelerator (Varian 600C/2100C Varian Medical Systems, Palo Alto, CA, USA). Data analysis Patients were seen weekly during the course of radiotherapy and 1 month after the completion of treatment. Subsequent follow-up was in an endocrine clinic with regular hormone pro®le assessment. Tumour control was de®ned by the absence of clinical and radiological progression and stable or decreasing hormone levels in secreting adenomas. The effect of therapy on Table 3 Endocrine assessment in secretory tumours No. of patients Acromegaly³ Normalized GH and IGF-1* Declining levels** GH > 104 mU/l remaining high Prolactinomas³ Normalized prolactin² Declining levels*** Lost to follow-up
6 1 4 1 4 1 2 1
*GH < 2 mU/l during oral glucose tolerance test and IGF 1 < 50 nmol/L; ² Prolactin < 480 mU/L; ³ includes mixed GH & PRL secreting; **GH levels 31´6 (r) 1´9 (2 months), 19 (r) 7 (4 months), 45±20 (4 months), 103 (r) 13´3 (5 months); 15´3 (r) 9´7 (5 months) [mU/l (month)]; ***PRL levels 5000 (r) 3´480 (12/12), 1288 (r) 657 (14/12) [mU/l (months)].
Table 4 Visual status of 22 patients with pituitary adenoma after SCRT Vision at presentation (number of patients)
Improvement
Unchanged
Deterioration
± 1 2
7 ± 2
± ± ±
6
4
2*
Normal vision (7) Impaired visual acuity (1) Visual ®eld defect (4) Impaired acuity and ®eld defect (10)
*Transient.
vision was assessed on serial ophthalmological examinations. Survival and progression-free survival were measured from the start of SCRT.
Results Local control and survival Twenty-two patients with residual and recurrent pituitary adenoma were treated with SCRT. The median follow-up was 9 months (range 1±44 months). Follow-up MRI imaging was available in 13 patients 1±26 months after treatment. There was a reduction in the size of the tumour in ®ve patients and no change in others. The 1 and 2 year actuarial progression free and overall survival are 100%. Effect of therapy in secretory tumours Endocrine assessment in patients with secretory adenomas is summarized in Table 3. Six patients had declining values of initially elevated hormones. One patient with mixed GH secreting tumour and prolactinoma had normalization of elevated GH with unchanged prolactin. One patient with GH > 104 mU/l remained with high level six months after treatment, and one patient was lost to follow-up (returned abroad). None of the patients with normalized or reducing hormone level had a subsequent rise. Effect of therapy on vision Fifteen patients had impaired vision prior to SCRT (Table 4). Improvement of vision after treatment was seen in nine patients. One patient had a mild transient deterioration in vision in the form of quadrantanopia two weeks after treatment and received a short course of corticosteroids with full recovery of vision. One patient had a visual deterioration seven months after treatment and an MRI revealed cystic degeneration of the residual pituitary mass impinging on the optic chiasm. Following cyst drainage, there was full recovery of vision q 2000 Blackwell Science Ltd, Clinical Endocrinology, 52, 695±702
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Table 5 Pituitary function of 22 patients with pituitary adenoma after SCRT Hypopituitarism Steroid axis Gonadal axis Thyroid Vasopressin
Pre-SCRT
Post-SCRT*
12 10 6 1
2/10 3/12 3/16 0/21
*Number of patients requiring replacement/number at risk.
which remains normal at the time of last follow up. Vision remained stable in all other patients. Adverse effects Most patients developed temporary localized alopecia at the beam entrance. Five patients developed mild transient postradiotherapy somnolence which recovered within 8 weeks of completion of treatment. Prospective assessment of cognitive function was not performed but none of the patients developed obvious memory impairment or neuropsychological dysfunction. No patient developed late visual de®cit attributable to radiotherapy. Endocrine function Six patients had panhypopituitarism at the time of SCRT and were on hormone replacement therapy. Of six patients with normal pituitary function prior to radiotherapy, two developed endocrine de®ciency at 5 and 6 months after SCRT requiring hormone replacement (one hydrocortisone, one hydrocortisone and testosterone). Two patients with steroid axis de®ciency alone at the time of SCRT required additional replacement with thyroxine and testosterone at 2 and 15 months, respectively, after treatment. One patient on oestrogen replacement required thyroxine 6 months after treatment (Table 5). Discussion There is considerable debate about the role of radiotherapy in the management of patients with pituitary adenoma. Nevertheless, radiotherapy is frequently used in patients with residual or recurrent tumours. Conventional fractionated external beam radiotherapy to doses of 45±55 Gy given over a period of 5± 6 weeks achieves long-term tumour control ranging from 80 to 97% at 10 years and 72±92% at 20 years (Urdaneta et al., 1976; Erlichman et al., 1979; Brada et al., 1993; McCollough et al., 1991; Grigsby et al., 1988; Breen et al., 1998; Tsang et al., 1996; Gittoes et al., 1998). Modern radiotherapy techniques deliver more precise and localized radiation than conventional radiotherapy with a q 2000 Blackwell Science Ltd, Clinical Endocrinology, 52, 695±702
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steeper dose gradient between high and low dose regions. Stereotactic radiosurgery/radiotherapy techniques involve ®rm and accurate immobilization with ®xed or relocatable frames, high precision 3-D target localization with CT/CT-MRI fusion and focused radiation delivery. This is achieved either with a multiheaded cobalt unit (gamma knife) or with multiple arcs using a modi®ed conventional linear accelerator. Such conventional stereotactic irradiation techniques typically produce spherical high dose volumes and are therefore suitable only for small spherical lesions (Graham et al., 1991b). A majority of pituitary adenomas considered for radiotherapy are not spherical and frequently extend to adjacent structures including the cavernous sinus, optic chiasm and sphenoid sinus. To treat large nonspherical volumes with conventional SRS requires the addition of multiple small spherical high dose volumes described as multiple isocentre treatment. The overlap of high dose spheres results in dose inhomogeneity which has been associated with a higher incidence of radiation induced complications (Nedzi et al., 1991). We have previously demonstrated that the optimum way of delivering high precision localized irradiation to larger nonspherical targets is with the use of multiple conformal ®xed ®elds with individualized shielding of each radiation ®eld conforming to the shape of the target (Laing et al., 1993a). This principle of conformal therapy combined with the precision of stereotactic localization and focused radiation delivery is described as stereotactic conformal radiotherapy. Traditionally stereotactic irradiation has been delivered in a single session as single fraction radiosurgery. High doses of radiation given in one fraction are known to be associated with a high risk of radiation induced damage to normal tissue and this is particularly true for the central nervous system (Sheline et al., 1980). Giving radiation in small individual doses allows the delivery of higher radiation doses without serious injury to the normal tissues which is especially important for normal CNS structures (Marks et al., 1981). Single fraction SRS is associated with considerable neurological toxicity to the optic apparatus (Tishler et al., 1993) (Leber et al., 1998) the cranial nerves (Leber et al., 1998; Engenhart et al., 1990) and normal brain (Mitsumori et al., 1998). With the advent of high precision relocatable noninvasive means of immobilization, it has become possible to deliver stereotactic irradiation in a fractionated manner (Laing et al., 1993b). The technique of SCRT combines the precision of focused radiation delivery and the radiobiological advantages of fractionation. It also ensures homogenous dose distribution within the irradiated volume further reducing the risk of damage. The aim of high precision SCRT is to achieve a high dose differential between the tumour and the surrounding normal tissues. This allows for either an increase in the tumour dose to improve local control or for a potential decrease in radiation damage to the normal tissues. As there is no clear bene®t in
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tumour control of pituitary adenomas with doses beyond 45±50 Gy (McCollough et al., 1991; McCord et al., 1997; Breen et al., 1998), the aim of SCRT is to achieve high tumour control rates seen with conventional radiotherapy while minimizing the risk of CNS injury from radiation. SCRT was therefore given to 45± 50 Gy in 25±30 daily fractions over a period of 5±6 weeks (®ve fractions per week) delivered at a standard dose per fraction of 1´67±1´8 Gy. Tumour control at relatively short follow-up is excellent within the range reported following conventional external beam radiotherapy. Longer follow-up is required to have full con®dence that the excellent early tumour control is retained. It has been suggested that in patients with secretory tumours single fraction SRS compared to fractionated radiotherapy produces a more rapid normalization of elevated hormone levels (Landolt et al., 1998; Yoon et al., 1998). The current reports of SRS are based on retrospective comparison with a cohort of patients treated with fractionated radiotherapy with ¯aws in the pretreatment matching of the hormone levels between the two treatment modalities and no information about the rate of decline of individual hormone levels (Jalali & Brada, 1999). While SRS may produce a faster decline in elevated hormone levels than fractionated radiotherapy, the evidence so far does not support the hypothesis and remains to be proven in prospective trials. The rate of normalization of the elevated hormone levels following SCRT is as would be expected following conventional fractionated radiotherapy with no increase in hormone levels. The follow-up is however, too short to be certain about long-term ef®cacy. The most commonly reported late morbidity of conventional radiotherapy is hypopituitarism with cumulative actuarial risk of 20±50% at 10±20 years (Shalet, 1981; Brada et al., 1993; Tsang et al., 1994). Hypopituitarism is likely to be due to the damage to both hypothalamus and pituitary, although the former is considered of primary importance (Samaan et al., 1975). Stereotactic irradiation techniques aim to reduce radiation dose to adjacent normal tissue. It has been suggested that this may lead to more effective preservation of normal pituitary function. The reported incidence of pituitary endocrine failure following SRS (Yoon et al., 1998; Mitsumori et al., 1998) is high within the range expected following conventional radiotherapy and this is also the case for SCRT. Despite the more localized nature of irradiation with SRS and SCRT, the doses of irradiation actually delivered to the hypothalamus are considerable. Further optimization studies are needed to develop techniques which minimize radiation doses to the hypothalamus. However damage to the pituitary gland may also contribute and none of the treatment techniques so far can avoid irradiating the residual glandular tissue in patients with macroadenomas. In the treatment of large nonspherical tumours, the optic apparatus is commonly included in the high dose volume of irradiation. Single fraction SRS to the optic pathways has been
associated with a high risk of damage (Tishler et al., 1993; Witt et al., 1996). The frequency of damage is dose dependent with 78% risk of optic neuropathy in patients receiving > 15 Gy and 27% risk for those receiving 10±15 Gy to the optic apparatus (Leber et al., 1998). The incidence of radiation induced visual impairment following conventional fractionated radiotherapy doses of 45±50 Gy in 25±30 fractions delivered at standard fractionation schedule over 5±6 weeks is 1±3% (Brada et al., 1993; McCord et al., 1997; Tsang et al., 1994). The lack of visual damage attributable to SCRT is therefore within the expected range for this small group of patients at a short follow-up. External beam irradiation is associated with the development of second radiation induced neoplasms with reported cumulative actuarial risk in patients with pituitary adenoma of 2±2´7% at 10±30 years (Brada et al., 1992; Breen et al., 1998; Tsang et al., 1993) not seen in all studies (Jones, 1991; Bliss et al., 1994). Localized radiotherapy techniques of SRS and SCRT may reduce the incidence of second tumours but are unlikely to eliminate it. To demonstrate a small reduction will require a very large number of patients and a long follow-up. Radionecrosis is a recognized complication of CNS radiotherapy usually to doses beyond conventional radiation tolerance (Aristizabel et al., 1977; Fontana et al., 1984; Fukamachi et al., 1982; Lampert et al., 1964). The term `radionecrosis' has been used inconsistently ranging from mild asymptomatic white matter parenchymal changes to frank pathologically proven necrotic masses (al Mefty et al., 1990) (Diengdoh et al., 1976) (Eyster et al., 1974) (Peck et al., 1966). The risk of radiation necrosis increases with dose, dose per fraction and volume of normal brain irradiated (Kramer, 1968) (Marks et al., 1981, 1985). Delayed brain parenchymal injury including radionecrosis following irradiation of pituitary tumours has been reported in lateral temporal lobes and is attributed to high dose regions using parallel opposed ®elds and the use of orthovoltage radiotherapy (al Mefty et al., 1990; Fontana et al., 1984). The incidence of radionecrosis with the use of modern technology with high energy megavoltage linear accelerators at standard dose-fractionation (< 50 Gy at < 2 Gy/ fraction) is extremely low (Sheline et al., 1980; Marks et al., 1981). Although SRS delivers localized irradiation to small volumes the single fraction doses are relatively large and have been associated with radionecrosis in temporal lobe in three out of 12 patients (28% actuarial risk at 3 years) (Mitsumori et al., 1998). There have been no cases of radionecrosis seen in patients treated with fractionated stereotactic radiotherapy (Mitsumori et al., 1998) and in the present study. High dose irradiation volumes in the temporal and frontal lobes with conventional radiotherapy techniques has been also widely believed to cause late neurocognitive dysfunction. Although formal cognitive function studies have failed to detect a de®nite impairment due to irradiation alone (Grattan Smith et al., q 2000 Blackwell Science Ltd, Clinical Endocrinology, 52, 695±702
Stereotactic conformal pituitary radiotherapy
1992; Peace et al., 1997), a mild radiation induced de®cit cannot be ruled out without a full prospective study (McCord et al., 1997). Minimizing the radiation dose to the normal brain tissue through SCRT has the potential of reducing the putative risk of cognitive impairment. No patient in the current study has developed a new neurocognitive abnormality so far although this was not formally tested. We conclude that stereotactic conformal radiotherapy is a practical and relatively easily applicable high precision localized irradiation treatment technique which can be incorporated in the daily routine of a busy radiotherapy department. The technique is suitable for the treatment of pituitary adenomas requiring radiotherapy. Early results in terms of local control and toxicity are comparable to conventional radiotherapy and longer follow-up is required to assess its true effectiveness in terms of sustained tumour control and reduction in treatment related toxicity. Acknowledgements The work was supported in part by the Neuro-Oncology Research fund, The Royal Marsden NHS Trust and the Cancer Research Campaign. We are grateful to our neurosurgical and endocrinology colleagues for their continued collaboration. This work was undertaken by the Royal Marsden NHS Trust who received a proportion of its funding from the NHS executive; the views expressed are those of the authors and not necessarily those of the NHS executive. References al Mefty, O., Kersh, J.E., Routh, A. & Smith, R.R. (1990) The long-term side effects of radiation therapy for benign brain tumors in adults. Journal of Neurosurgery, 73, 502±512. Alexander, E., 3rd, Kooy., H.M., van Herk, M., Schwartz, M., Barnes, P.D., Tarbell, N., Mulkern, R.V., Holupka, E.J. & Loef¯er, J.S. (1995) Magnetic resonance image-directed stereotactic neurosurgery: use of image fusion with computerized tomography to enhance spatial accuracy. Journal of Neurosurgery, 83, 271±276. Alheit, H., Saran, F.H., Warrington, A.P., Rosenberg, I., Perks, J., Jalali, R., Shepherd, S., Beardmore, C., Baumert, B. & Brada, M. (1999) Stereotactically guided conformal radiotherapy for meningiomas. Radiotherapy and Oncology, 50, 145±150. Aristizabel, S., Caldwell, W.L. & Avila, J. (1977) The relationship of time dose fractionalism factors to complications in the treatment of pituitary tumours by irradiation. International Journal of Radiation, Encology, Biology and Physics, 2, 667±673. Bliss, P., Kerr, G.R. & Gregor, A. (1994) Incidence of second brain tumours after pituitary irradiation in Edinburgh 1962±90. Clinical Oncological Royal College of Radiology, 6, 361±363. Bloom, H.J.G. (1973) Radiotherapy of pituitary tumours. In: Pituitary Tumours, (Jenkins, J.S., ed.) pp. 186±189. Butterworths, London. Brada, M., Ford, D., Ashley, S., Bliss, J.M., Crowley, S., Mason, M., Rajan, B. & Traish, D. (1992) Risk of second brain tumour after conservative surgery and radiotherapy for pituitary adenoma. British Medical Journal, 304, 1343±1346. q 2000 Blackwell Science Ltd, Clinical Endocrinology, 52, 695±702
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