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McCune-Albright Syndrome and Acromegaly: Effects of Hypothalamopituitary Radiotherapy and/or Pegvisomant in Somatostatin Analog-Resistant Patients

Assistance Publique-Hôpitaux de Paris, Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Service d’Endocrinologie et des Maladies de la Reproduction (F.G., P.K., H.A., J.Y., P.C.), Hôpital de Bicêtre, 94275 Le Kremlin-Bicêtre, France; Service d’Endocrinologie (Y.R.), Centre Hospitalier Universitaire Côte de Nacre, 14033 Caen, France; Département de Radiothérapie (D.P.), Institut Curie, 75005 Paris, France; Institut National de la Santé et de la Recherche Médicale U693 (P.K., J.Y., P.C.), 94276 Le Kremlin-Bicêtre, France; Assistance Publique-Hôpitaux de Paris, Laboratoire d’Explorations Fonctionnelles Endocriniennes (Y.L.B.), Hôpital Trousseau, 75012 Paris, France; and Université Paris-Sud 11 (J.Y., P.C.), 94275 Le Kremlin-Bicêtre, France

Address all correspondence and requests for reprints to: Philippe Chanson, M.D., Service d’Endocrinologie et des Maladies de la Reproduction, Hôpital de Bicêtre, 78 rue du Général Leclercqq, 94275 Le Kremlin-Bicêtre, France. E-mail: philippe.chanson{at}bct.aphp.fr.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Background: Acromegaly, which may be present in patients with McCune-Albright syndrome (MCAS), in association with café-au-lait spots, precocious puberty, and fibrous dysplasia, is often difficult to treat surgically because skull base bone dysplasia prevents the removal of the pituitary adenoma. Somatostatin analogs (SAs) generally give only partial responses. The use of radiotherapy (RT) is controversial because of a possible risk of bone sarcomatous transformation.

Aim: This study was a retrospective analysis of the efficacy and adverse effects of different treatment modalities in six patients with both MCAS and acromegaly.

Patients and Methods: Because surgery was impossible and SA failed to normalize GH/IGF-I hypersecretion, five of the six patients received fractionated RT (45–55 Grays). Three patients (two with previous RT) were also prescribed pegvisomant. We analyzed the clinical features of acromegaly, GH, and IGF-I concentrations and bone radiological features.

Results: GH and IGF-I concentrations fell after RT (median follow-up, 5 yr; range, 0.5–9 yr). Symptoms of acromegaly improved in parallel. Bone sarcomatous transformation was only noted in one patient in a region (the mandible) outside the radiation field. RT alone and/or combined with SA failed to normalize GH/IGF-I levels in the five patients concerned. In contrast, IGF-I levels normalized very rapidly (5–9 months) in the three patients receiving pegvisomant (10–20 mg/d).

Conclusion: RT may be an option for the treatment of acromegaly in patients with MCAS when surgery is impossible and SA therapy is ineffective. However, although no bone sarcomatous transformation was observed within the radiation field in this series, this risk cannot be ruled out. As shown in this small series of severely affected patients, pegvisomant therapy may thus be useful to normalize IGF-I levels rapidly.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
THE ORIGINAL DESCRIPTION of McCune-Albright syndrome (MCAS) included the triad of poly-/monostotic fibrous dysplasia, café-au-lait spots, and precocious puberty. This syndrome affects various endocrine tissues that develop autonomous function of cells responding to extracellular signals through activation of the hormone-sensitive adenylate cyclase system. Several mutations in exon 8 of the GNAS gene have been detected in affected endocrine organs of patients with MCAS (1). MCAS is occasionally associated with GH hypersecretion (2, 3), and treatment of such patients is difficult because skull involvement frequently prevents neurosurgical excision and because radiotherapy (RT) may possibly cause bone sarcomatous transformation (4, 5, 6, 7). The efficacy of somatostatin analogs (SAs) in these patients is only partial (2, 3, 8, 9, 10, 11). We describe six cases of acromegaly and MCAS in which RT and/or pegvisomant were used to achieve normal IGF-I levels because of partial SA resistance.

	Patients and Methods

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Patients

We studied all six patients with acromegaly and MCAS who were managed in Hôpital de Bicêtre. Demographic and clinical data are reported in Table 1. Surgery was possible in patient 1, but the tumor was only partially removed. SAs [octreotide, sc or long acting release (LAR), or lanreotide prolonged release (PR)] were started in five patients, and the doses were gradually increased. Five of the six patients also received fractionated RT (45–55 Gy). Pegvisomant was prescribed to three patients, of whom two were previously irradiated. Some data on patients 1, 2, 4, and 5 have been reported elsewhere (3).

GH and prolactin (PRL) serum levels were measured with commercial kits. Reported basal GH serum levels are the mean of at least four values obtained during an hourly profile.

Until 1998, serum IGF-I concentrations were measured according to methods previously reported (12). Serum samples were gel filtered on columns of Ultrogel AcA54 in acetic acid to separate IGFs from their binding proteins. RIA was used to assay IGF-I using the specific polyclonal antihuman IGF-I antibody (generous gift from Drs. Closset, Frankenne, and Hennen, Liège, Belgium). Recombinant human IGF-I (generously provided by CIBA-GEIGY Ltd., Basel, Switzerland) was used both as standard and as tracer. Unknown samples were studied at three concentrations, each in duplicate plus one blank (tube without antibody). Intra- and interassay coefficients of variation are 4.8 and 10%, respectively. Since 1998, the same IGF-I RIA was carried out after separating IGF from the binding proteins, according to a new method. Briefly, plasma samples (25 µl) were incubated for 30 min at room temperature in an acidic medium (0.01 N HCl) and then ultrafiltered on Centricon 30 (Amicon, Epernon, France). After lyophilization, the ultrafiltrate containing IGF was taken up in 0.1 M phosphate buffer (0.1% BSA, pH 7.4) and assayed in the same RIA with the same antibody. The IGF recovery was around 90% in the ultrafiltrate, which contained no detectable amounts of IGF-binding proteins as measured by Western ligand blotting. An excellent positive correlation between the plasma IGF-I values was obtained with both methods (r² = 0.94; n = 187). With the C30 ultrafiltration method, the reference IGF-I concentrations were similar as previously described (12). Mean ± SD of serum IGF-I (in µg/liter) according to age are as follows: 16–20 yr old, 405 ± 70; 20–30 yr old, 310 ± 55; 30–40 yr old, 275 ± 50; 40–50 yr old, 245 ± 50; 50–60 yr old, 215 ± 50; 60–70 yr old, 185 ± 50; 70–80 yr old, 165 ± 50; and >80 yr old, 155 ± 50. SD scores were calculated as the ratio of the difference between the observed level and the mean to the SD using age-specific reference ranges obtained for our IGF-I assay. The IGF-I level is considered normal when the IGF-I SD score (SDS) is between –2 and +2. Values exceeding 5 were considered not relevant to provide individual IGF-I SDS.

Pituitary irradiation

A median total dose of 50 Gy (range, 45–55 Gy) was given at a rate of 1.8 Gy daily, 5 d/wk. A variety of treatment techniques and beam energies were used, depending on the date of RT, as follows: 1.25-MV rays from a ⁶⁰Co source with a three-field arrangement (left and right lateral and anterior portals) in 1980 (patient 1) and 15- to 23-MV x-ray beams produced by a linear accelerator in the following five cases. Three of the latter five patients (patients 2–4) were treated at the Curie Institute between 1995 and 2000 with a conformal treatment planning procedure and a 15-MV x-ray beam. The target volume was defined on lateral and anterior simulation films guided by radiological and surgical findings and, after 1994, with contrast-enhanced computed tomography scans, in a treatment position guided by radiological findings. Five coplanar and eight and seven noncoplanar fixed-beam techniques were used successively to spare surrounding normal tissues. The total dose ranged from 45–50 Gy (ICRU) to minimize bone irradiation, taking into account the possible increased risk of radiation-induced sarcoma in this setting (13).

Follow-up

After irradiation, patients were checked for clinical manifestations and GH and IGF-I concentrations at 6-month intervals. An expert radiologist carefully examined skull base CT and magnetic resonance imaging (MRI) scans at 6- to 12-month intervals to detect bone sarcomatous transformation. SA treatment was always pursued at the same dose after RT.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
Basal clinical and biochemical results

The six patients with MCAS had typical active acromegaly, as shown by high serum GH levels (11–48 µg/liter, not suppressed by OGTT) and increased IGF-I levels (Tables 1 and 2).

Clinical and hormonal responses to SA (Table 2 and Fig. 1)

Clinical features. SA therapy did not improve the symptoms of acromegaly.

View larger version (31K): [in this window] [in a new window]   FIG. 1. Course of individual serum GH (upper panel) and IGF-I SDS (lower panel) levels in six patients with MCAS and acromegaly successively treated with SAs and/or RT and/or pegvisomant.

All five patients were thus considered totally or partially resistant to SA, whatever the mode of administration, the dose, or the duration of treatment.

Clinical and hormonal responses to RT

After RT, medical treatment with SA was maintained in all patients at the maximal doses given before RT.

Clinical features. Symptoms of acromegaly improved gradually after RT. Sweating normalized. Glycemic control improved in the two diabetic patients. Pain and bone deformations due to fibrous dysplasia remained unchanged, and patient 4 underwent facial surgery to reduce the deformities.

Hormonal responses (Table 2 and Fig. 1). A marked reduction in GH and IGF-I concentrations was observed in all the patients. However, none of the five irradiated patients saw their GH/IGF-I levels normalize during follow-up, despite continued SA treatment in four cases.

Bone imaging. Regular cranial bone CT and MRI showed no evidence of bone sarcomatous transformation of the fibrous dysplasia within the field of irradiation, even after a follow-up of 9 yr (patient 2). Patient 4 had sarcomatous transformation of bone fibrous dysplasia in the right mandible, which was outside the field of irradiation (performed 5 yr previously).

Impact of pegvisomant

Clinical features. All three patients felt a clear benefit. In patient 3, the carpal tunnel syndrome disappeared, and glucose tolerance improved, allowing oral hypoglycemic agents to be discontinued.

Hormonal responses. IGF-I concentrations normalized on pegvisomant in all three patients (Table 2). No adverse effects were noted during 15–24 months of follow-up. MRI surveillance of the pituitary gland showed no increase in the size of the adenoma.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
Because surgical removal of the adenoma was impossible, and RT may possibly cause sarcomatous transformation in patients with fibrous dysplasia, we tried medical therapy first. Octreotide has been reported to reduce, and sometimes to normalize, GH/IGF-I hypersecretion in patients with acromegaly and MCAS (2, 3, 8, 9, 10, 11). This study confirms and extends our previous observations (3) because all our patients were resistant to SA, probably because they were very severely affected. This led us to propose RT in some cases because no medical alternative was available (pegvisomant was not marketed at the time). RT was very effective on clinical manifestations and on hormone levels but failed to normalize GH/IGF-I levels. Because GH/IGF-I levels remained increased under SA, we never stopped them and thus never tested the effects of RT alone. Regular skull CT and MRI scans, particularly within the field of irradiation, showed no evidence of sarcomatous transformation of fibrous dysplasia. Only isolated cases of such transformation have been described (4, 6, 7, 14). In the experience of the Mayo Clinic (6), only 28 of 1122 patients with histologically confirmed fibrous dysplasia developed a sarcoma, and only half of them had previously received RT. In this series, the only patient with MCAS who developed sarcomatous transformation had not received RT. Rare cases of spontaneous sarcomas within fibrous dysplasia, without prior RT, have also been described (15, 16, 17, 18, 19). Spontaneous sarcomatous transformation was observed in one of our patients, in an area outside the field of irradiation used for the pituitary adenoma.

Although RT may be an interesting option for patients with SA-resistant acromegaly and MCAS, follow-up is often too short to conclude on the potential risk of malignant transformation of fibrous dysplasia.

We decided to test pegvisomant, a GH antagonist highly effective in patients with acromegaly (20), particularly in the case of SA resistance. As expected, the treatment was very effective on IGF-I levels. Low doses of pegvisomant were necessary, possibly because of previous RT in two cases.

In conclusion, RT may be an interesting therapeutic option for severely affected patients with acromegaly and MCAS when surgical removal of the pituitary adenoma is hindered by skull base fibrous dysplasia and when SA therapy is ineffective. However, although no cases of bone sarcomatous transformation of fibrous dysplasia within the field of irradiation were observed in this short series, the risk cannot be ruled out. Moreover, the efficacy of RT is slow and only partial. Pegvisomant therapy may thus be interesting to normalize IGF-I levels rapidly.

	Footnotes

 
The work did not receive any specific financial support. The Service d’Endocrinologie et des Maladies de la Reproduction, Université Paris-Sud 11, receives unrestricted educational and research grants from Novartis, Ipsen, and Pfizer. F.G., P.K., H.A., Y.R., D.P., Y.L.B., and J.Y. have nothing to declare. P.C. received consulting and lecture fees from Novartis, Ipsen, and Pfizer.

First Published Online September 19, 2006

Abbreviations: LAR, Long acting release; MCAS, McCune-Albright syndrome; MRI, magnetic resonance imaging; PR, prolonged release; PRL, prolactin; RT, radiotherapy; SA, somatostatin analog; SDS, SD score; tid, three times a day.

Received March 13, 2006.

Accepted September 8, 2006.

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Top Abstract Introduction Patients and Methods Results Discussion References

 

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