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Stereotactic Radiosurgery XVI: A Treatment for Previously Irradiated Pituitary Adenomas

Departments of Endocrinology (F.M.S., C.A.A., S.L.C., A.B.G., G.M.B., J.P.M.), Radiotherapy (P.N.P., A.S.), and Radiology (J.E.), St. Bartholomew’s and The Royal London School of Medicine, London EC1A 7BE, United Kingdom

Address all correspondence and requests for reprints to: Professor J. P. Monson, M.D., F.R.C.P., Department of Endocrinology, St. Bartholomew’s and The Royal London School of Medicine, Queen Mary University of London, West Smithfield, London EC1A 7BE, United Kingdom. E-mail: j.p.monson{at}qmul.ac.uk.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
We report the use of stereotactic radiosurgery delivered through an adapted linear accelerator [stereotactic multiple arc radiation therapy (SMART)] for pituitary adenomas not cured by conventional therapy. All 21 patients had undergone conventional radiotherapy (45–50 Gy); 18 had also undergone prior surgery. This cohort comprised 13 patients with somatotrope adenomas, four with corticotrope adenomas, one with a lactotrope adenoma, and three with nonfunctioning pituitary adenomas (median follow-up: 33 months, range: 3–72 months).

SMART has proven effective, safe, and rapidly acting. We observed an accelerated reduction in GH and IGF-I levels in acromegaly, with normalization of GH and IGF-I levels in 58%. Mean GH fell from 21.1 mU/liter to 7.9 mU/liter (7 ng/ml to 2.6 ng/ml, P < 0.01, median 25 months) faster than our predicted fall to 50% at 2 yr with conventional radiotherapy. Mean IGF-I fell from 624 ng/ml to 384 ng/ml (P < 0.001). Tumor growth was controlled in two of three nonfunctioning pituitary adenomas, and three of four corticotrope adenomas.

There were no adverse effects from SMART. Notably there have been no visual sequelae or further loss of anterior pituitary function in this heavily pretreated group. Our data indicate that SMART is an effective complementary therapy for pituitary adenomas that have displayed a suboptimal response to conventional therapy including external irradiation.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
DESPITE IMPROVEMENTS IN imaging and in neurosurgical techniques, many patients with pituitary tumors will not be cured after transsphenoidal surgery. Up to 60% of patients with acromegaly and 40% of patients with Cushing’s disease continue to show biochemical evidence of disease after surgery (1, 2, 3, 4, 5), which is frequently treated by means of conventional megavoltage radiotherapy. Patients with macroadenomas presenting with chiasmal compression or cavernous sinus involvement and patients with nonfunctioning pituitary adenomas have also traditionally been offered postoperative radiotherapy due to the high rate of disease persistence (6, 7, 8).

Conventional radiotherapy can indeed be very effective (9). In acromegaly, GH levels can be expected to fall by up to 50% of preradiotherapy levels at 2 yr and in 70% of patients continue to fall for up to 15 yr (10, 11). Radiotherapy also effects a progressive decline in hormone levels in other functioning tumors. Sixty percent of patients with Cushing’s disease achieved clinical remission by 18 months in one series (12), 50% of patients with Nelson’s syndrome normalize serum ACTH levels at a median of 9.5 yr (13, 14), and 50% of prolactinomas achieved normalization of serum prolactin (PRL) levels at a median of 8 yr (15).

However, the effects of radiotherapy may take several years to develop, and further conventional radiotherapy is contraindicated due to the accumulated radiation exposure of surrounding structures (hypothalamus and optic pathways). As a consequence, prolonged medical therapy or repeated surgery may be required but may not always be feasible.

Stereotactic radiosurgery represents high-precision local irradiation given in one session. When this focused irradiation is given in more than one fraction the term stereotactic radiotherapy is used. Such irradiation can be delivered using a proton acclerator, the knife, or through a conventional linear accelerator (16, 17, 18) and may be delivered with very low exposure to the surrounding normal brain. This relies on high-quality imaging data from contrast enhanced magnetic resonance imaging (MRI) to delineate the size and shape of the lesion, as well as CT and plain radiographs to map the surrounding anatomy and define the target location. Stereotactic software is then used to coordinate precise radiation delivery to the target, while effectively sparing the surrounding normal tissue. Our unit has extensive experience of a conventional linear accelerator (Linac) based radiosurgery using stereotactic multiple arc radiotherapy (SMART) for other intracranial focal lesions such as hemangioblastoma (19), and we now report its use in recurrent refractory pituitary adenomas.

In the decade from 1989–1999, we have delivered SMART to 21 patients with somatotrope, corticotrope, lactotrope, and nonfunctioning pituitary adenomas who had evidence of continued disease activity despite surgery on at least one occasion as well as conventional radiotherapy and medical treatment. This is the first series to look exclusively at previously irradiated patients with persisting disease.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
Patients

Patient details are summarized in Table 1 and indications for SMART are summarized in Table 2. Twenty-one patients with pituitary macroadenomas attending the Department of Endocrinology at St. Bartholomew’s Hospital, London, received SMART between 1989 and 1999. Follow-up data are available for 20 patients (patient 13 was discharged home abroad and has been unable to return for assessment). The mean age at time of treatment was 48 yr (range 18–67 yr). Thirteen patients had acromegaly, four had an initial diagnosis of Cushing’s disease with two subsequently developing Nelson’s syndrome, three had nonfunctioning pituitary adenomas, and one patient had a macroprolactinoma. All but three patients (all with acromegaly) had received pituitary surgery on at least one occasion: eight patients had undergone pituitary surgery twice and two patients on three occasions. All three patients who did not undergo primary surgery were referred from other institutions, and it is unclear why primary surgery had not been performed. All patients had received conventional radiotherapy: 45–50 Gy in 25–40 fractions, using a three-field linear accelerator technique, before receiving SMART. The mean intervening period between conventional radiotherapy and stereotactic radiotherapy was 109 months with a median 80 months (the patients who received radiotherapy as a primary treatment had intervals between conventional and stereotactic radiotherapy of 11, 69, and 247 months.

Imaging revealed abnormal tissue in the cavernous sinus in 14 patients, in the sphenoid sinus in five patients and tissue largely confined to the pituitary fossa in 11 patients. All the tumors were at least 5 mm from the optic chiasm.

Methods of clinical assessment

All patients had a baseline evaluation including clinical review with visual perimetry, contrast enhanced MRI of the pituitary, investigation of basal endocrine function and dynamic testing with insulin or glucagon tolerance tests to seek deficiencies of the remaining anterior pituitary hormones. Sixteen patients underwent insulin tolerance testing in which 0.15 U soluble insulin/kg was given iv to achieve hypoglycemia of less than 2.2 mmol/liter. Where hypoglycemia was inadequate a repeat dose of 0.15 U/kg insulin was administered. A rise in serum cortisol of more than 170 nmol/liter to at least 580 nmol/liter was defined as normal, and a GH peak above 9 mU/liter (3 ng/ml) was taken to exclude severe GH deficiency (20, 21). Where insulin tolerance testing was contraindicated due to ischemic heart disease or epilepsy, glucagon testing was performed. One milligram of glucagon (1.5 mg if patient weight over 90 kg) was administered sc. Normal responses were defined in the same way as those of the insulin tolerance test (22).

Somatotrope tumors

Disease activity was assessed using the mean of a five-point serum GH day curve and a serum IGF-I concentration. Levels were considered within normal limits if the mean GH value was less than 5 mU/liter (<1.7 ng/ml) and IGF-I within the age-related reference range (age 30–49, 120–339 ng/ml; age 50–59, 108–263ng/ml; age 60–70, 108–229 ng/ml) (23). Patients 1–8, 11, and 13 were maintained on long-term medical therapy before SMART, with patients 1–4 partly responsive and the remainder highly responsive to somatostatin analog therapy (patients 1, 7, and 11 were receiving long-acting somatostatin analog therapy). Patients 10 and 12 did not tolerate therapy well and were only poorly responsive, whereas patient 9 was responsive to therapy but unable to obtain regular supplies. Patients 1, 2, 9, 10, 12, and 13 had all assessments performed off all treatment. Long-acting somatostatin analogs were stopped for at least 6 wk before all assessments. Patients 3–8 and 11 remained on somatostatin analog therapy throughout the period of study, and so these patients had all assessments performed on treatment.

Corticotrope tumors

Activity was assessed using the mean of a five-point serum cortisol day curve (mean values of 150–300 nmol/liter indicate normal cortisol production rate) and by an ACTH level 120 min after the hydrocortisone dose at 0900 h for the two patients with Nelson’s syndrome (normal value <18 pmol/liter) (13, 24). None of these patients were on medical therapy at the time of assessment.

Lactotrope tumors

Single serum PRL measurements off medical treatment were used in the patient with a prolactinoma (normal range < 400 mU/liter).

At the start of the study, 11 patients were on glucocorticoid replacement, four were on GH, 13 were on T₄, 10 were on estrogen, and eight were on testosterone replacement therapy. Six of 13 patients with acromegaly were on full hormone replacement therapy, and five of eight patients with other diagnoses were also panhypopituitary on dynamic testing. Estrogen therapy was stopped for 6 wk before any cortisol measurements in all patients.

All patients were reassessed similarly at 3 months and then at 6-month intervals. The most recent available measurements are given for IGF-I follow-up.

All hormonal measurements were performed in the Department of Chemical Endocrinology, St Bartholomew’s Hospital. Serum IGF-I was measured by standard RIA after formic acid/acetone extraction (25). ACTH was also measured by a specific RIA (26). Serum cortisol and PRL were assayed using the Bayer Immuno1 autoanalyzer, and GH was assayed using the Immulite human GH kit.

Each patient had an MRI scan to evaluate the site and volume of disease before SMART and CT scanning was subsequently performed for planning purposes. Scans were repeated 3 months after SMART and then at 12-month intervals; sequential scans were assessed together by the same neuroradiologist (J.E.).

Method of SMART delivery and planning

We used a Linac adapted for stereotactic delivery of radiation therapy using isocentric mounting and rotation technology (17, 27, 28). The targets were mapped by three-dimensional coordinates using both plain radiographs and CT. Patients were deemed unsuitable for SMART if their tumor lay within 3 mm of the optic chiasm. The target was then placed at the Linac isocenter. The accelerator emits x-rays through special secondary collimators making multiple noncoplanar arcs around the target. This leads to accumulation of dose to the target with a rapid fall off of dose from the target edge. Up to five 140-degree arcs were used. To create a steeper dose gradient along one edge of target, usually to spare the chiasm, two or three more closely clustered near horizontal arcs were used to affect a more extreme dose gradient rostrally. Isodosimetry was calculated using X-knife software (Radionics, Boston, MA) and doses were modified to take into account previous exposure of the chiasm to conventional radiotherapy (28). During the planning stage for patients 19 and 20, it became apparent that the optic chiasm had already been exposed to a large dose of ionizing radiation and so a relocatable stereotactic frame was used in conjunction with the Linac to allow delivery via two or three fractions. These two patients therefore received stereotactic radiotherapy but did not receive radiosurgery. The SMART doses administered varied between 8 and 15 Gy as shown in Table 1. The modal dose delivered was 10 Gy. The doses selected are lower than in other radiosurgical publications where radiosurgery has been used as the primary radiation method and reflect the dose limit to the optic chiasm of 3.0 Gy. This restriction was introduced by ourselves for this previously irradiated group, where the optic chiasm has already received partial radiation tolerance.

The protocol for administering SMART is based on outpatient management. In view of the proximity of the radiation target to the optic chiasm and the theoretical risk of post irradiation edema, 2 h before the stereotactic radiotherapy patients received 4 mg dexamethasone, and this was continued every 6 h for 36 h after treatment.

Patients were not taken off medical therapy specifically for SMART such that 10 of 13 patients with acromegaly received irradiation during somatostatin analog therapy. Patients 9, 10, 12, and 14–21 were therefore on no medical therapy at the time of receiving SMART.

Statistical analysis

Comparisons of measurements before and after SMART were performed using paired Student’s t tests (Microsoft Excel).

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
Clinical indications and their response to SMART are summarized in Table 2. The results for patients with acromegaly are summarized in Figs. 1 and 2 and all other data are summarized in Table 3.

View larger version (14K): [in this window] [in a new window]   FIG. 1. Time course of the reduction in mean serum GH (the mean value of a five-point GH day curve) after SMART in patients with acromegaly.

View larger version (11K): [in this window] [in a new window]   FIG. 2. The reduction in serum IGF-I after SMART in individual patients with acromegaly.

Biochemical follow-up data are available for 12 of 13 patients with acromegaly. All of these patients showed a reduction in disease activity. Follow-up ranged from 3–48 months (median 25 months) for this group.

Serum GH

Seven patients (58%) achieved mean serum GH levels within normal limits (<5 mU/liter, <1.7 ng/ml) after SMART (patients 4–7, 9, 11, 12). Six of these were able to stop all other therapy (patient 4 has normal GH on medical therapy). For all patients, a reduction in the mean value of a GH day curve is seen within 6 months of SMART. The range of mean GH before SMART was 5.4–60.7 mU/liter, with a mean value 21.1 mU/liter (1.8–20.2 ng/ml, mean 7 ng/ml); post SMART the range was 1.9–26.4 mU/liter, mean value 7.85 (0.3–8.8 ng/ml, mean 2.6 ng/ml) (P < 0.01). The timescale of response to SMART for all patients is shown in Fig. 1.

Serum IGF-I

Of the 11 patients in whom pre and post SMART IGF-I levels were available, a reduction was also evident in all as shown in Fig. 2: pre SMART range 220-1281 ng/ml, mean 623.5 ng/ml; post SMART range 99–965 ng/ml, mean 383.9 ng/ml (P < 0.001). Six patients (55%) achieved normal IGF-I levels after SMART (patients 4, 5, 7, 9, 11, and 12), five of whom remain off all treatment. Patient 11 had near normal IGF-I and GH levels on octreotide before SMART but was able to normalize both and come off treatment post SMART (pre SMART 420 ng/ml, post SMART 218 ng/ml, age-related reference range:120–330 ng/ml). Patient 12 had elevated GH levels and serum IGF-I at the upper end of the age-related reference range: 232 ng/ml, normal range: 108–263 ng/ml and was highly symptomatic before SMART. IGF-I level fell to 123 ng/ml, GH normalized and her symptoms improved dramatically post SMART (jeweler’s ring measurement reduced by three sizes at 12 months). Of the three patients in whom the indication for SMART was pain in addition to disease activity, two experienced relief of this specific symptom within 1 wk of therapy (5, 12).

Ten of the 13 patients with somatotrope adenomas required somatostatin analog therapy before SMART (patients 1–8, 11, and 13). After SMART, doses were reduced in three patients (3, 4, and 8) and stopped in four patients (patients 5, 6, 7, and 11).

MRI scanning of the patients with acromegaly showed little change in the size of their residual tumor (>50% reduction in patient 5, 20% reduction in patient 13, no obvious change on review of all previous scans for the remaining patients as shown in Table 1). The mean follow-up time to latest scan was 20.1 months with a range of 3–36 months, although regular scanning continues.

Efficacy: corticotrope tumors

Follow-up data were available to 6 months in all patients and are summarized in Table 3. Both patients with active Cushing’s disease reported an improvement in their clinical condition, although there was little change in their circulating cortisol levels (mean cortisol decreased in patient 14, increased in patient 15). Plasma ACTH levels fell in both patients. One of the patients with Nelson’s syndrome also improved clinically with an early fall in ACTH (patient 16). Tumor size on MRI did not change in these patients.

Efficacy: lactotrope tumors

The single patient with an aggressive prolactinoma received SMART on two occasions to two distinct disease sites—a left orbital extension and a subsequent retrosellar extension. Initial treatment to the left orbit resulted in relief of pain, improvement in third nerve palsy and a fall in serum PRL. At assessment 7 months later, this area of disease had improved on MRI scanning, although there was a new retrosellar focus. She then underwent chemotherapy and subsequent SMART to this area of disease. Her clinical condition again initially improved, but her disease progressed with death due to cardiorespiratory arrest attributable to brain stem extension.

Efficacy: nonfunctioning pituitary tumors

Patient 20 responded radiologically to SMART (10% reduction in size) and neither patient 19 nor 20 have required further surgery since. However, patient 18 continued to suffer from severe headaches and imaging confirmed disease progression necessitating further surgery.

Safety

One patient (no. 19) experienced an exacerbation of his severe headache for 48 h after SMART which subsequently resolved. There have been no other adverse effects. No visual sequelae have been detected by visual perimetry or acuity testing in any of the patients treated to date (follow-up 3–72 months, median 33 months). There has been no change in residual anterior pituitary function as assessed by annual dynamic testing in the 10 patients who were not panhypopituitary before receiving SMART (follow up 3–36 months, mean 16 months). Cognitive function, cranial nerve function, and memory have not been formally assessed in this patient cohort, but no adverse effects have been reported or detected on annual clinical review. On-going surveillance continues with annual contrast enhanced MRI scanning to seek tumor regrowth or the development of second tumors. None have so far been detected.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
We present the first detailed data examining the use of radiosurgery as a salvage treatment for patients with pituitary tumors who have effectively exhausted all conventional treatments. All patients had received at least 45 Gy of conventionally fractionated radiotherapy, and 86% had also undergone pituitary surgery. We report an accelerated reduction in GH and IGF-I levels in all patients with acromegaly, with 50% cure (median follow-up 25 months post radiosurgery).

Our data suggest that radiosurgery in the form of SMART may be a useful treatment for patients with acromegaly. Stringent criteria for cure have been applied, with treatment only deemed successful if IGF-I is reduced to within the age-related reference range for that subject, and the mean value of 5 GH measurements taken throughout the day is less than 5 mU/liter (1.7 ng/ml) (a full discussion of definitions of satisfactory response/cure are given in Ref.23). Only at this stage is the patient considered to have normal GH and IGF-I levels, and treatment reduction or cessation considered. The median interval between conventional radiotherapy and SMART was 104 months (mean 80 months) in this group, and the fall in GH and IGF-I levels appeared to have reached plateau phase. All patients showed a further fall in GH and IGF-I after SMART. Half of the patients achieved normal levels of both IGF-I and GH levels for the first time since diagnosis (mean time since diagnosis 15 yr), and 58% achieved normalization of either GH or IGF-I. Nine patients also reported a noticeable improvement in symptoms.

Patients were taken off medical treatment for all assessments where possible. However, treatments were not stopped specifically for the delivery of SMART, such that 76% of patients received radiotherapy during somatostatin analog therapy. A recent study has suggested that octreotide confers a radioprotective effect on somatotrope tumors treated with radiosurgery (29). In that series the knife system was used, and none of the tumors had received prior irradiation; however, its conclusions might have more general applications. In this series, only three patients were not on somatostatin analog therapy at the time of radiosurgery, and two of these achieved GH and IGF-I levels within normal limits (patients 9 and 12). Of the 76% patients who were on somatostatin analog therapy at the time of SMART, 60% normalized GH levels, whereas 40% normalized IGF-1 levels. It is possible that had medical therapy been stopped before SMART as recommended by the Landolt group, the effects may have been more dramatic still. However, this would require long acting somatostatin analog therapy to be stopped 4 months before SMART, sc octreotide used in its place and all therapy ceased 2 wk before SMART to ensure adequate washout.

The patients presented in this series represent tumors highly resistant to conventional therapy, although disease severity varied significantly as shown in Figs. 1 and 2. The most dramatic falls in GH and IGF-I levels are observed in those patients with the most severe disease, whereas cure and the ability to reduce or stop somatostatin analog therapy is more frequently achieved in those patients with less severe disease (patients 4–13). We suggest then that radiosurgery has a somatostatin analog sparing role: allowing patients with severe disease to finally achieve normal GH/IGF-I levels on their continued medical therapy, and may allow cessation of medical therapy with continued normal levels in patients with less severe disease. At the time of SMART, 10 patients required ongoing medical treatment; somatostatin analog therapy has now been stopped in 40% and reduced in 30%.

There was virtually no tumor shrinkage detected on MRI scanning in this series: to date there has been modest improvement in two of 13 patients with acromegaly, and one of three patients with nonfunctioning pituitary tumors only. Longer follow-up should resolve this issue, although it is noteworthy that in a separate series tumor shrinkage on CT or MRI bore no relation to GH level reduction (30).

There was little objective benefit in the patients with Cushing’s disease. Corticotropes are less radiosensitive than GH secreting cells (31, 32) and in view of the previous radiation exposure of the pituitary and surrounding tissue, the doses of SMART used were low (modal marginal dose 10 Gy). Previous groups have used higher doses of radiosurgery with more dramatic falls in ACTH secretion, but have incurred a greater risk of neurological or pituitary damage (31, 33, 34, 35, 36).

Thus far we have treated only one patient with a macroprolactinoma. This patient is not typical. The tumor had become resistant to dopamine agonist therapy with widespread local invasion. There was an initial response to SMART consistent with the reports of Levy (37); however, these data are insufficient to draw objective conclusions.

Finally, the excellent safety profile of SMART is noteworthy. These patients were heavily pretreated before SMART so that the lack of progression of anterior pituitary failure on dynamic testing to date in the 10/21 patients not already pan-hypopituitary is surprising. However, in this previously irradiated group, it is the lack of visual or other complications which is particularly impressive, and contrasts with other published series using Linac-based (38) or knife radiosurgery (30, 34, 35, 39). This also contrasts with the proton beam, which has been heralded as more precise and thus capable of delivering higher and more effective doses of irradiation particularly for large and superficial intracranial targets (37, 40). A review of 98 patients receiving proton beam radiosurgery for cavernous malformations reported a 16% incidence of permanent neurological deficit and 3% mortality rate secondary to radiotherapy (41).

The disparity between the safety profile of this series and others may be due to tumor selection: all were at least 5 mm from the optic chiasm on MRI imaging, or may reflect conservative dosing by our unit with dose modification to restrict chiasm exposure to less than 3 Gy. Use of microcollimation for conformational linear accelerator based radiosurgery should enable this excellent safety record to continue in the future, whereas efficacy continues to improve.

Conclusions

In summary, stereotactic radiosurgery in the form of SMART, has been highly effective in the treatment of 12 patients with acromegaly persisting despite previous surgery and conventional radiotherapy. Fifty-five percent of patients with acromegaly have achieved normalization of IGF-I, and 50% have normalized both IGF-I and GH (median follow up 25 months). Only one transient adverse effect was noted in the 21 patients treated (headache). There has been no deterioration in anterior pituitary function on annual dynamic function testing, and no adverse visual, cerebrovascular or cranial nerve sequelae have been detected with follow-up to 48 months. This safety profile compares favorably with other published series of radiosurgery and is particularly noteworthy as this is a previously irradiated group. Recurrent corticotrope, lactotrope, and nonfunctioning pituitary adenomas were also treated with SMART, but no objective benefit was observed in these tumors.

	Footnotes

 
Abbreviations: Linac, Conventional linear accelerator; MRI, magnetic resonance imaging; PRL, prolactin; SMART, stereotactic multiple arc radiation therapy.

Received March 6, 2002.

Accepted August 18, 2003.

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