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Clinical Studies |
Section of Endocrinology, Medical Department B (A.K.F., J.H., J.J.) and Department of Neuroradiology (S.B.), Rikshospitalet, University of Oslo, Oslo, Norway; and Sandoz Pharma Ltd. (I.L., P.M., C.B.), Basel, Switzerland
Address all correspondence and requests for reprints to: Dr. Anette Kvistborg Fløgstad, Section of Endocrinology, Medical Department B, Rikshospitalet, 0027 Oslo, Norway.
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Subjects and Methods |
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The patients (Table 1
; eight women and six men) had a
median age of 52 yr (range, 27–69 yr), a median weight of 76.3 kg
(range, 45.0–117.0 kg), a median height of 173.3 cm (range,
155.5–192.0 cm), and a median duration of acromegaly from time of
diagnosis of 4.8 yr (range, 0.3–20 yr). Four patients were newly
diagnosed acromegalics. Ten had undergone either pituitary surgery
and/or external pituitary irradiation, six had received bromocriptine,
and one patient had received long term treatment with octreotide. All
patients were good responders (suppression of mean GH to 50% of basal
levels and/or to <5 µg/L) to octreotide (100 or 200 µg) given sc
three times daily and had previously received either a single (20 or 30
mg) or two (3, 6, 9, or 12 mg and 20 or 30 mg) injections of
Sandostatin LAR im in a dose-response study (4).
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The baseline GH (means of 12 hourly obtained GH values between 0800–2000 h) and IGF-I (means of IGF-I values obtained at 0800 0900 h) values obtained during the dose-range study (4) were are also used as baseline values in the present study. During the present study the patients were evaluated on the 28th day after every im injection of Sandostatin LAR. Assessments of 8-h (hourly between 0800–1600 h) GH and octreotide profiles (hourly for the first six injections, only two samples at 0800 and 0900 h thereafter) and IGF-I measurements (two samples at 0800 and 0900 h), as well as registration of adverse events and acromegaly-related signs and symptoms were performed on all study days. Acromegaly-related signs and symptoms (headache, fatigue, perspiration, paresthesia, joint pains, and carpal tunnel syndrome) were rated on a 5-point scale (0, absent; 1, mild; 2, moderate; 3, severe but not incapacitating; 4, severe and incapacitating). Physical examination and standard laboratory analysis were performed at baseline and after every sixth injection. Echographic examination of the gallbladder and biliary system and measurements of glycosylated hemoglobin A1C (HbA1C), TSH, T3, and free T4 were performed at baseline and after every third injection.
Oral glucose tolerance tests were performed before the start of the study and after the 12th and 18th injections of Sandostatin LAR. CT or magnetic resonance imaging (MRI) scan of the pituitary gland was performed at baseline and after every sixth injection. Standardized meals were served on all study days at 1000 and 1300 h.
IGF-I levels were measured by RIA (Nichols Institute Diagnostics, San Juan Capistrano, CA; normal range, 65–500 µg/L), GH was determined by a double monoclonal antibody technique (Delfia Kit, Wallac OY, Turku, Finland), and octreotide concentrations were measured by RIA (Biopharmaceutical Department, Drug Safety Assessment of Sandoz Pharma, Basel, Switzerland), as previously described (4, 13). Insulin and C peptide levels were measured by RIAs (Diagnostic Product Corp., Los Angeles, CA).
Standard methods were used for assessment of clinical chemistry parameters. CT scans of the pituitary were performed with the patient in the coronal position after bolus contrast injection (100 mL; Omnipaque 300, Nycomed, Oslo, Norway) using a Somatom DR (Siemens, Erlangen, Germany). Tumor size was estimated from continuous 2-mm scans through the pituitary region. Sagittal and coronal T1 weighted (TR 600/TE 20) MRI scans of the pituitary tumor were obtained without, and in most patients also with, contrast injection (Magnevist, Schering, Berlin, Germany) using a Siemens Magnetom 63, (Siemens, Erlangen, Germany). The scan parameters were 3 mm slices/0.3 mm distance. The greatest length, height, and width (in centimeters) of the pituitary tumor were measured, and the product of these measurements was considered an index of tumor size (in cubic centimeters). No attempt was made to correct for irregularities in tumor shape when estimating this index. Because this study is still ongoing, the results for tumor size assessments after 24 months are included.
Data analysis
The GH, IGF-I, and octreotide data determined on each profile day are presented for each individual as a daily mean. A t test or a paired t test was used for testing statistical significance between groups. For correlation analysis, a Spearman rank order test was used. P < 0.05 was considered significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The effect of Sandostatin LAR on daily mean GH levels during all
study days (Fig. 1) and as an average for the entire
study period (Fig. 2) for each patient are presented.
During the entire study period, daily means of GH were, on the average,
suppressed below 2 µg/L in nine, to between 2–5 µg/L in three, and
to between 5–10 µg/L in two patients. GH was stable and consistently
suppressed during the treatment period (Fig. 3), except
in one patient, whose mean daily GH varied from 4–10 µg/L. The
standard deviations in mean GH (mean of the daily average GH) for each
study subject varied between 0.1–0.8 µg/L.
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). However, in the
individual patient, the increment of the dosage of Sandostatin LAR to
above 20 mg was not associated with improved suppression of GH (Table 2). There was a positive correlation between mean GH and mean IGF-I
levels both pretreatment (r = 0.64; P = 0.015) and
during treatment with Sandostatin LAR im (r = 0.64,
P = 0.015).
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The effect of Sandostatin LAR on daily mean IGF-I levels during
all study days (Fig. 1
) and the average during the entire study period
(Fig. 2) for the individual patients are presented. Daily means of
IGF-I were, on the average, suppressed to below 500 µg/L (normal
range) in nine patients and to between 500-1000 µg/L in the remaining
five patients. Except for one patient, who showed a gradual decrease in
mean daily IGF-I from 1049 to 681 µg/L, which was not associated a
concomitant GH reduction, the intrasubject fluctuation in daily mean
IGF-I during treatment, was low. The individual SDs for
mean IGF-I (mean of the daily mean IGF-I values) varied between 30–100
µg/L (Fig. 3). Twenty, 30, and 40 mg Sandostatin LAR suppressed IGF-I
compared to basal values (Table 2). Although an increase of dosage from
20 to 30 mg was associated with a decline in IGF-I, a further increase
to 40 mg was not (Table 2).
Octreotide
Mean serum octreotide concentrations after injection of the
different doses of Sandostatin LAR are shown in Table 2. Daily mean
octreotide levels fluctuated both in the individual patient and among
the patients after injection of similar dosages. Individual
SDs for mean octreotide (mean of the daily mean octreotide)
varied between 231-2333 ng/L (17–72% of the mean octreotide levels).
Increasing the dosage of Sandostatin LAR caused an increase in the
average serum concentration in the individual patient (Table 2).
Clinical evaluation
Regardless of the dosage administered, the acromegalic sign and
symptom score improved during im treatment with Sandostatin LAR (Table 2). Neither GH, IGF-I, nor serum octreotide levels correlated with the
symptom score or the improvement in symptom score during treatment.
Tumor size
A greater than 20% reduction in tumor size was seen in the four
previously untreated patients (Fig. 4). In two of these,
tumor size reduction was gradual and continuous throughout the
treatment period, whereas the other two patients responded with a major
tumor reduction within the first 6 months of treatment. Of the
previously treated patients, three had no visual residual tumor, and
seven showed no definitive tumor shrinkage.
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Three patients discontinued study medication prematurely. One patient (no. 1) had a cerebral infarction after 11 injections. She had a history of breast cancer and hypertension and was a heavy smoker. Another patient discontinued the study in preference for a second pituitary operation after six injections (patient 5). The third patient discontinued study due to gastrointestinal complaint and loss of scalp hair after four injections (patient 10). Transient hair loss during Sandostatin LAR treatment was also experienced by another patient (patient 8).
One patient taking 0.1 mg T4 daily experienced a single episode of atrial fibrillation after alcohol intake. One patient developed gallstones during treatment. He has slightly elevated alkaline phosphatase, but is asymptomatic and continues treatment with Sandostatin LAR. Dilatation of the gallbladder and/or biliary ducts (2 patients) and sludge in the gallbladder (1 patient) were found on ultrasound examination during treatment. In all 3 patients, the last echographic examination was described as normal. An additional 3 patients had polypoid lesions in the gallbladder at inclusion that did not progress during treatment. The remaining 8 patients had normal echographic examinations of both gallbladder and bile ducts. Intermittent, mild to moderate gastrointestinal complaints, most commonly loose stools and flatulence, were reported by 12 of the 14 patients during the first 6 months of treatment and by 8 of the 12 patients during the last 12 months of treatment. One patient acquired anemia and vitamin B12 deficiency during treatment with Sandostatin LAR. Gastroscopy revealed no abnormality, and parietal cell antibodies were not found. Since then, the patient has received substitution treatment with vitamin B12, and hemoglobin levels are within the normal range. Evaluation of TSH, total and free T4, and T3 serum concentrations in the remaining patients did not reveal any impairment of thyroid function (mean ± SD of TSH varied between 1.0 ± 0.7 and 1.3 ± 1.0 mU/L; mean ± SD of T3 varied between 1.6 ± 0.2 and 1.8 ± 0.3 nmol/L; mean ± SD of free T4 varied between 16.2 ± 2.8 and 17.1 ± 4.0 pmol/L). Clinical chemistry safety indexes showed no pathological changes.
Local tolerability at the injection site was good in most patients. Transient (1–2 days), mild to moderate pain at the injection site was occasionally reported by 10, swelling by 4, and rubor by 1 patient, but did not cause discontinuation of the study medication.
Glucose tolerance
One patient was treated with glibenklamide for diabetes mellitus
at entry into the study. HbA1C increased initially from
6.3% to 7.8%, but returned to pretreatment values after a period of
intensified drug and diet treatment and suppression of GH. Another
patient who had diabetic glucose tolerance but normal HbA1C
at the start of the study showed no change in glucose tolerance during
treatment with Sandostatin LAR. In a third patient oral glucose
tolerance deteriorated, but her HbA1C remained within the
normal range. Two patients dropped out of the study before reevaluation
of oral glucose tolerance. In the remaining patients, mean values of
fasting glucose, peak glucose, and 2-h glucose values during oral
glucose tolerance testing were similar before and during im treatment
with Sandostatin LAR (Fig. 5). Their corresponding
HbA1C (mean ± SD before treatment,
5.7 ± 0.5%; after 12 months, 5.4 ± 0.5%; after 18 months,
5.6 ± 0.5%) also remained unchanged during treatment. Insulin
and C peptide values obtained during oral glucose tolerance testing
after 12 and 18 months of treatment were similar.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Octreotide inhibits GH, insulin, and glucagon (17). In acromegaly, many of the actions of excess GH on carbohydrate metabolism are antagonistic to insulin (18). Successful octreotide treatment of acromegalics improves insulin sensitivity and counterbalances the inhibition of insulin secretion (19). Both beneficial effects on glucose tolerance in acromegalics with glucose intolerance as well as impairment of metabolic control during octreotide treatment are described (3, 20, 21, 22). We found only minor changes in glucose metabolism in the nondiabetic acromegalic patients during treatment with Sandostatin LAR. In one patient with noninsulin-dependent diabetes mellitus at entry into the study, a transient impairment of metabolic control was seen.
Our findings of tumor size reduction in 4 of the 14 patients during treatment is in agreement with previous reports during sc treatment with Sandostatin (1, 2, 3, 5, 6, 7, 9, 10, 11). Radiological identification of a pituitary tumor in patients previously treated by surgery or irradiation may be difficult, and we were unable to find any effect of Sandostatin LAR on tumor size in such patients. However, in accordance with the results of preoperative sc treatment of acromegalic patients with octreotide (8) and previous experience with Sandostatin LAR (4, 12), we found tumor size reduction in all previously untreated patients during im treatment with Sandostatin LAR.
Although most patients had gastrointestinal complaints initially, a noticeable reduction of this side-effect occurred with time. This observation is in agreement with reports on long term sc treatment with octreotide (9, 10, 11). One of our patients acquired vitamin B12 deficiency during treatment. A decrease in vitamin B12 levels in acromegalic patients during sc treatment with octreotide has previously been reported (23). In the present study only one patient developed asymptomatic gallstones after 18 months of treatment. This is in accordance with previous reports on sc treatment with octreotide (1, 2, 3), in which 4–18% of the subjects developed gallstones during long term treatment. The significant loss of scalp hair seen in two of our patients was also previously reported during sc treatment with octreotide for acromegaly (24).
In summary, long term treatment with Sandostatin LAR effectively ameliorates symptoms and reduces GH and IGF-I consistently in octreotide-sensitive acromegalic patients. Our experience after more than 24 months of treatment substantiate this impression. In previously untreated patients it also reduces pituitary tumor size. The drug is well tolerated during long term treatment.
Sandostatin LAR may well be the future medical treatment of choice for acromegalic patients.
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Acknowledgments |
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Footnotes |
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Received March 22, 1996.
Revised July 31, 1996.
Accepted August 5, 1996.
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