Clinical Endocrinology (1992) 36, 147-150
Pituitary imaging using a labelled somatostatin analogue in acromegaly E. Ur, S. J. Mather", J. Bomanjl', D. Ellison', K. E. Brltton', A. B. Grossman, J. A. H. Wass and G. M. Besser Departments of Endocrinology and 'Nuclear Medicine, St Bartholomew's Hospital, London UK (Received 8 July 1991; returned for revision 16 August 1991; finally revised 17 September 1991; accepted 8 October 1991)
Summary OBJECTIVE A number of neoplasmsare known to express somatostatin receptors, and the use of somatostatin receptor imaging in their localization has recently been described. We have looked at the use of an 1231-iabeiied TyP-octreotideanalogue of somatostatin in the visuallzation and functional characterization of growth hormonesecreting pituitary adenomas. PATIENTS Fifteen patients with biochemically-proven acromegaly were scanned using this agent. In eight of these we ~ i s assessed o acute GH responses to octreotide in order to correlate these responses with tumour uptake characteristics. MEASURES Planar and single-photon-emission computerized tomographic (SPECT)images of the head were obtained using a gamma-camera at 10 minutes, and 4 and 24 hours, after Injectionof the radiopharmaceutical.Blood for serum GH was sampled for 12 hours after administration of a single dose of 100 pg octreotide. RESULTS Twelve of the acromegaiic subjects showed significant uptake of the radiopharmaceutical in the pitultary fossa. Of the eight patients in whom we assessed acute GH responses, five demonstrateda significant fall in GH in response to octreotide. These subjects also showed positive uptake in the pituitary on scanning. The three patients who had no fall In GH had no uptake on scanning. CONCLUSIONS Uptake of '231-labeiledTyr3-octreotide in the pituitary fossa appears to correlate closely with the presence of a therapeutic response to octreotide.
A wide variety of neoplasms have been reported to have high affinity binding sites for the peptide hormone somatostatin: these include growth-hormone secreting pituitary adenomas Correspondence: Dr Ehud Ur, Department of Endocrinology, St Bartholomew's Hospital, West Smithfield. London ECIA 7BE, UK.
(Reubi & Landolt, 1984), meningiomas, astrocytomas, neuroblastomas (Reubi et al., 1987) and breast cancers, as well as pancreatic and carcinoid tumours (Reubi et al., 1987). Such receptors are thought to mediate the inhibition of hormonal secretion from some of these tumours (Kvols et al., 1986). They may also mediate the inhibition of tumour growth (Lamberts et al., 1987). Octreotide, an eight aminoacid residue analogue of somatostatin, is effective in producing long-term suppression i f GH in most acromegalic patients and is a valuable therapeutic agent. A synthetic, tyrosine) substituted variant of octreotide has been developed for the purpose of radiolabelling with IZ3I. This derivative, SDZ 204-090, is actively taken up at somatostatin binding sites: thus, after radioiodination, this compound (Iz3I-SDZ)can be used for in-vivo localization of tumours with a gamma-camera (Krenning et al., 1989).
Materials and methods
Fifty micrograms of the somatostatin analogue Tyr3-octreotide (Sandoz, Basel, Switzerland) were labelled with approximately 200 MBq of lz31 by electrophilic substitution using Iodogen. The labelled material was then purified by passage down a sterile ion-exchange column (Dowex 1x8) and sterilized by filtration through a 0.22-pm filter (Millipore, Milford, Mass, USA). Labelling efficiency and radiochemical purity before and after purification were assessed by reverse phase HPLC radiochromatography. Before each study, 120 mg/day of potassium iodide were administered orally, starting 24 hours prior to scintigraphy and continued up to 48 hours post-injection in order to block thyroid uptake of 12)I. For scanning, 1231-SDZwas given as a bolus intravenous injection at a dose of up to 250 MBq. This resulted in an effective dose equivalent of 4.4 mSv.
Scanning
Planar and single-photon-emission computerized tomographic (SPECT) images of the head were obtained at 10 minutes, and 4 and 24 hours, after injection of the radiopharmaceutical, using a large-field-of-view gamma-camera interfaced to a DEC PDPl l-44 computer (Counterbalance 3700, Siemens Gammasonics, Erlangen, Germany). Positive uptake was defined as the presence of pituitary uptake in at least three serial slices on transaxial scanning (slice thickness 147
148
E. U r e t a f .
Clinical Endocrinology (1992) 36
Table 1 Patient details, result of scanning after '2'1-labelled Tyrloctreotide. and clinical response to octreotide in 15 acromegalic
patients
Patient
Sex
Age ~~
I 2
F F
3 4
M
5
M M M M
F
6 7 8 9 10
I1 I2* 12t I3 14 15
49 64 61
58
F
M
60
F F F F
56
M
Acute GH response
+
+ + + +
~
52
63 53 34 39
IVI
Scan response
52 52 M 59 41
+ + +
+ +
+ + + + + +
-
+
NA NA NA NA NA NA NA NA
NA. not assessed. Scan response: + signifies uptake in the region of the pituitary in more than three sequential transaxial slices on SPECT scanning. Acute GH response: + signifies fall of > 50% compared to mean basal level. Preoperation. t Post-operation.
0.7 cm). Scans were assessed independently, without knowledge of the diagnosis or of the results of other imaging modalities, by two nuclear medicine clinicians (JB, KEB).
~erienrs Fifteen patients with acromegaly were included in the study, which had been approved by the St Bartholomew's Hospital District Ethical Committee. All subjects gave their informed consent. Diagnosis of acromegaly was confirmed by failure of suppression of elevated GH to less than 1 mU/I during a 75-g oral glucose tolerance test. Thirteen of the subjects were naive to octreotide (Sandoz, Easel, Switzerland). The other two (subjects 5 and 14) had had several weeks of treatment some months previously, and had been off octreotide for at least one month prior to the study.
~
We assessed acute GH responses to octreotide in eight of the patients prior to scanning in an attempt to correlate acute G H responses with tumour uptake characteristics. These patients were given octreotide 100 pg subcutaneously at 0830 h. Blood for G H determination was taken at 0830 and 0900 h and thence at hourly intervals for 12 hours, and were compared with values obtained in a similar way without octreotide. The serum GH assay was performed using a standard IRMA kit (NETRIA, London, UK). All subjects had been off octreotide therapy for at least one week prior to sampling. One patient (no. 12) underwent trans-sphenoidal hypophysectomy and was re-scanned 3 weeks post-operatively. Suppression in response to octreotide was defined as a fall in serum GH to less than 50% of basal values. Results
Full patient details, the results of scanning after '231-labelled Tyr3-octreotide, and clinical response to octreotide are shown in Table I . Of the 15 patients, 12 showed clear uptake in the region of the pituitary whilst three showed no uptake. Planar and SPECT images of the head in a non-acromegalic subject are shown in Fig. 1. Significant uptake can be seen in the parotids and oropharynx. Comparable images from a patient with acromegaly demonstrating extensive uptake around the pituitary fossa are shown in Fig. 2. Serum growth hormone responses to a single subcutaneous dose of octreotide (Fig. 3) revealed lowering in excess of 50% in five out of eight patients. These subjects all showed positive uptake in the pituitary fossa on somatostatin scanning. Three subjects who showed less than a 50% fall in GH in response to octreotide had no uptake on scanning. Pre and postoperative scans as well as the difference image of one patient who underwent trans-sphenoidal hypophysectomy are shown in Fig. 4. This patient's mean serum growth hormone (determined from five blood samples obtained through a day) fell from a preoperative mean level of 3 15 mU/1 to 10.5 mU/I 3 weeks post-operatively when she was re-scanned. Dlacusrlon
Labelled somatostatin analogue scanning provides a technique for the visualization and characterization of pituitary tumours in acromegaly. The only report in the literature on somatostatin scanning in pituitary tumours is from
~
Fig. 1 a, Planar and b, SPECT images of the head in a non-acromegalic patient. There is no uptake of the labelled octreotide in the region of the pituitary. Fig. 2 a. Planar and b, SPECT images of the head in an acromegalic patient. There is extensive uptake of the labelled octreotide around the pituitary fossa. Fig. 4 Pre and post-operative scans and the difference image of the acromegalic patient who
underwent trans-sphenoidal hypophysectomy.
Clinical Endocrinology (1992) 36
Pituitary imaging with somatostatin analogue
149
150
E. Ur et al.
Clinical Endocrinology (1992) 36
300
200 a
h
\
3
E
c
I W
Ioc
C
0
2
4
6
8
10
12
Time ( h ) Fig. 3 Growth hormone responses to a single 100-pg subcutaneous dose of octreotide in eight acromegalic patients. 0,Scan negative; 0 , scan
positive.
Lamberts et al. (1990). They described three patients with acromegaly secondary to pituitary adenomas, all of whom had positive uptake on radiolabelled somatostatin scanning: they did not report the biochemical responses to octreotide. In our preliminary study, 12 of 15 previously untreated acrOmegalics showed positive uptake using the technique. Those who did not take up the radiolabelled material failed to show a significant acute lowering in GH levels in response to the administration of a test dose of octreotide. Uptake of '231-labelled Tyr3-octreotide in the pituitary fossa thus appears to correlate closely with the presence of a neuroendocrine response to octreotide. This is most probably a reflection of the presence or absence of somatostatin receptors on the tumour, and may possibly be used as a guide to therapy. In the patient tested before and after surgery positive uptake in the pituitary disappeared in line with the marked fall in serum GH as a result of surgery.
References Krenning, E.P., Bakker, W.H., Breeman, W.A.P., Koper, J.W.,
Kooij, P.P.M.,Ausema, L., Lameris, J.S., Reubi, J.C. & Lamberts, S.W.J. (1989) Localisation of endocrine-related tumours with radio-iodinated analogue of somatostatin. Lancet, i, 242244. Kvols, L.K., Moertel, C.G., O'Connell, M.J., Schut, A.J., Rubin, J . & Hahn, R.G. (1986) Treatment of the malignant carcinoid syndrome: evaluation of a long-acting somatostatin analogue. New England JournaI of Medicine, 315, 663-666. Lamberts, S.W.J., Bakker, W.H., Reubi, J.C. & Krenning, E.P. (1990) Somatostatin-receptor imaging in the localisation of endocrine tumors. New England Journal of Medicine, 323, 12461249. Lamberts, S.W.J., Koper, J.W. & Reubi, J.C. (1987) The potential role of somatostatin analogs in the treatment of cancer. European Journal of Clinical Investigation, 17,28 1-287. Reubi, J.C. & Landolt, A.M. (1984) High density of somatostatin receptors in pituitary tumours from acromegalic patients. Journal of Clinical Endocrinology and Metabolism, 59, 1148-1 153. Reubi, J.C., Lang, W., Maurer, R., Koper, J.W. & Lamberts, S.W.J. (1987) Distribution and biochemical characterization of somatostatin receptors in tumours of the human central nervous system. Cancer Research, 47, 5758-5764.
Pituitary imaging using a labelled somatostatin analogue in acromegaly E. Ur, S. J. Mather", J. Bomanjl', D. Ellison', K. E. Brltton', A. B. Grossman, J. A. H. Wass and G. M. Besser Departments of Endocrinology and 'Nuclear Medicine, St Bartholomew's Hospital, London UK (Received 8 July 1991; returned for revision 16 August 1991; finally revised 17 September 1991; accepted 8 October 1991)
Summary OBJECTIVE A number of neoplasmsare known to express somatostatin receptors, and the use of somatostatin receptor imaging in their localization has recently been described. We have looked at the use of an 1231-iabeiied TyP-octreotideanalogue of somatostatin in the visuallzation and functional characterization of growth hormonesecreting pituitary adenomas. PATIENTS Fifteen patients with biochemically-proven acromegaly were scanned using this agent. In eight of these we ~ i s assessed o acute GH responses to octreotide in order to correlate these responses with tumour uptake characteristics. MEASURES Planar and single-photon-emission computerized tomographic (SPECT)images of the head were obtained using a gamma-camera at 10 minutes, and 4 and 24 hours, after Injectionof the radiopharmaceutical.Blood for serum GH was sampled for 12 hours after administration of a single dose of 100 pg octreotide. RESULTS Twelve of the acromegaiic subjects showed significant uptake of the radiopharmaceutical in the pitultary fossa. Of the eight patients in whom we assessed acute GH responses, five demonstrateda significant fall in GH in response to octreotide. These subjects also showed positive uptake in the pituitary on scanning. The three patients who had no fall In GH had no uptake on scanning. CONCLUSIONS Uptake of '231-labeiledTyr3-octreotide in the pituitary fossa appears to correlate closely with the presence of a therapeutic response to octreotide.
A wide variety of neoplasms have been reported to have high affinity binding sites for the peptide hormone somatostatin: these include growth-hormone secreting pituitary adenomas Correspondence: Dr Ehud Ur, Department of Endocrinology, St Bartholomew's Hospital, West Smithfield. London ECIA 7BE, UK.
(Reubi & Landolt, 1984), meningiomas, astrocytomas, neuroblastomas (Reubi et al., 1987) and breast cancers, as well as pancreatic and carcinoid tumours (Reubi et al., 1987). Such receptors are thought to mediate the inhibition of hormonal secretion from some of these tumours (Kvols et al., 1986). They may also mediate the inhibition of tumour growth (Lamberts et al., 1987). Octreotide, an eight aminoacid residue analogue of somatostatin, is effective in producing long-term suppression i f GH in most acromegalic patients and is a valuable therapeutic agent. A synthetic, tyrosine) substituted variant of octreotide has been developed for the purpose of radiolabelling with IZ3I. This derivative, SDZ 204-090, is actively taken up at somatostatin binding sites: thus, after radioiodination, this compound (Iz3I-SDZ)can be used for in-vivo localization of tumours with a gamma-camera (Krenning et al., 1989).
Materials and methods
Fifty micrograms of the somatostatin analogue Tyr3-octreotide (Sandoz, Basel, Switzerland) were labelled with approximately 200 MBq of lz31 by electrophilic substitution using Iodogen. The labelled material was then purified by passage down a sterile ion-exchange column (Dowex 1x8) and sterilized by filtration through a 0.22-pm filter (Millipore, Milford, Mass, USA). Labelling efficiency and radiochemical purity before and after purification were assessed by reverse phase HPLC radiochromatography. Before each study, 120 mg/day of potassium iodide were administered orally, starting 24 hours prior to scintigraphy and continued up to 48 hours post-injection in order to block thyroid uptake of 12)I. For scanning, 1231-SDZwas given as a bolus intravenous injection at a dose of up to 250 MBq. This resulted in an effective dose equivalent of 4.4 mSv.
Scanning
Planar and single-photon-emission computerized tomographic (SPECT) images of the head were obtained at 10 minutes, and 4 and 24 hours, after injection of the radiopharmaceutical, using a large-field-of-view gamma-camera interfaced to a DEC PDPl l-44 computer (Counterbalance 3700, Siemens Gammasonics, Erlangen, Germany). Positive uptake was defined as the presence of pituitary uptake in at least three serial slices on transaxial scanning (slice thickness 147
148
E. U r e t a f .
Clinical Endocrinology (1992) 36
Table 1 Patient details, result of scanning after '2'1-labelled Tyrloctreotide. and clinical response to octreotide in 15 acromegalic
patients
Patient
Sex
Age ~~
I 2
F F
3 4
M
5
M M M M
F
6 7 8 9 10
I1 I2* 12t I3 14 15
49 64 61
58
F
M
60
F F F F
56
M
Acute GH response
+
+ + + +
~
52
63 53 34 39
IVI
Scan response
52 52 M 59 41
+ + +
+ +
+ + + + + +
-
+
NA NA NA NA NA NA NA NA
NA. not assessed. Scan response: + signifies uptake in the region of the pituitary in more than three sequential transaxial slices on SPECT scanning. Acute GH response: + signifies fall of > 50% compared to mean basal level. Preoperation. t Post-operation.
0.7 cm). Scans were assessed independently, without knowledge of the diagnosis or of the results of other imaging modalities, by two nuclear medicine clinicians (JB, KEB).
~erienrs Fifteen patients with acromegaly were included in the study, which had been approved by the St Bartholomew's Hospital District Ethical Committee. All subjects gave their informed consent. Diagnosis of acromegaly was confirmed by failure of suppression of elevated GH to less than 1 mU/I during a 75-g oral glucose tolerance test. Thirteen of the subjects were naive to octreotide (Sandoz, Easel, Switzerland). The other two (subjects 5 and 14) had had several weeks of treatment some months previously, and had been off octreotide for at least one month prior to the study.
~
We assessed acute GH responses to octreotide in eight of the patients prior to scanning in an attempt to correlate acute G H responses with tumour uptake characteristics. These patients were given octreotide 100 pg subcutaneously at 0830 h. Blood for G H determination was taken at 0830 and 0900 h and thence at hourly intervals for 12 hours, and were compared with values obtained in a similar way without octreotide. The serum GH assay was performed using a standard IRMA kit (NETRIA, London, UK). All subjects had been off octreotide therapy for at least one week prior to sampling. One patient (no. 12) underwent trans-sphenoidal hypophysectomy and was re-scanned 3 weeks post-operatively. Suppression in response to octreotide was defined as a fall in serum GH to less than 50% of basal values. Results
Full patient details, the results of scanning after '231-labelled Tyr3-octreotide, and clinical response to octreotide are shown in Table I . Of the 15 patients, 12 showed clear uptake in the region of the pituitary whilst three showed no uptake. Planar and SPECT images of the head in a non-acromegalic subject are shown in Fig. 1. Significant uptake can be seen in the parotids and oropharynx. Comparable images from a patient with acromegaly demonstrating extensive uptake around the pituitary fossa are shown in Fig. 2. Serum growth hormone responses to a single subcutaneous dose of octreotide (Fig. 3) revealed lowering in excess of 50% in five out of eight patients. These subjects all showed positive uptake in the pituitary fossa on somatostatin scanning. Three subjects who showed less than a 50% fall in GH in response to octreotide had no uptake on scanning. Pre and postoperative scans as well as the difference image of one patient who underwent trans-sphenoidal hypophysectomy are shown in Fig. 4. This patient's mean serum growth hormone (determined from five blood samples obtained through a day) fell from a preoperative mean level of 3 15 mU/1 to 10.5 mU/I 3 weeks post-operatively when she was re-scanned. Dlacusrlon
Labelled somatostatin analogue scanning provides a technique for the visualization and characterization of pituitary tumours in acromegaly. The only report in the literature on somatostatin scanning in pituitary tumours is from
~
Fig. 1 a, Planar and b, SPECT images of the head in a non-acromegalic patient. There is no uptake of the labelled octreotide in the region of the pituitary. Fig. 2 a. Planar and b, SPECT images of the head in an acromegalic patient. There is extensive uptake of the labelled octreotide around the pituitary fossa. Fig. 4 Pre and post-operative scans and the difference image of the acromegalic patient who
underwent trans-sphenoidal hypophysectomy.
Clinical Endocrinology (1992) 36
Pituitary imaging with somatostatin analogue
149
150
E. Ur et al.
Clinical Endocrinology (1992) 36
300
200 a
h
\
3
E
c
I W
Ioc
C
0
2
4
6
8
10
12
Time ( h ) Fig. 3 Growth hormone responses to a single 100-pg subcutaneous dose of octreotide in eight acromegalic patients. 0,Scan negative; 0 , scan
positive.
Lamberts et al. (1990). They described three patients with acromegaly secondary to pituitary adenomas, all of whom had positive uptake on radiolabelled somatostatin scanning: they did not report the biochemical responses to octreotide. In our preliminary study, 12 of 15 previously untreated acrOmegalics showed positive uptake using the technique. Those who did not take up the radiolabelled material failed to show a significant acute lowering in GH levels in response to the administration of a test dose of octreotide. Uptake of '231-labelled Tyr3-octreotide in the pituitary fossa thus appears to correlate closely with the presence of a neuroendocrine response to octreotide. This is most probably a reflection of the presence or absence of somatostatin receptors on the tumour, and may possibly be used as a guide to therapy. In the patient tested before and after surgery positive uptake in the pituitary disappeared in line with the marked fall in serum GH as a result of surgery.
References Krenning, E.P., Bakker, W.H., Breeman, W.A.P., Koper, J.W.,
Kooij, P.P.M.,Ausema, L., Lameris, J.S., Reubi, J.C. & Lamberts, S.W.J. (1989) Localisation of endocrine-related tumours with radio-iodinated analogue of somatostatin. Lancet, i, 242244. Kvols, L.K., Moertel, C.G., O'Connell, M.J., Schut, A.J., Rubin, J . & Hahn, R.G. (1986) Treatment of the malignant carcinoid syndrome: evaluation of a long-acting somatostatin analogue. New England JournaI of Medicine, 315, 663-666. Lamberts, S.W.J., Bakker, W.H., Reubi, J.C. & Krenning, E.P. (1990) Somatostatin-receptor imaging in the localisation of endocrine tumors. New England Journal of Medicine, 323, 12461249. Lamberts, S.W.J., Koper, J.W. & Reubi, J.C. (1987) The potential role of somatostatin analogs in the treatment of cancer. European Journal of Clinical Investigation, 17,28 1-287. Reubi, J.C. & Landolt, A.M. (1984) High density of somatostatin receptors in pituitary tumours from acromegalic patients. Journal of Clinical Endocrinology and Metabolism, 59, 1148-1 153. Reubi, J.C., Lang, W., Maurer, R., Koper, J.W. & Lamberts, S.W.J. (1987) Distribution and biochemical characterization of somatostatin receptors in tumours of the human central nervous system. Cancer Research, 47, 5758-5764.
