Download Efficacy of the long-acting octreotide formulation (sandostatin

Efficacy of the long-acting octreotide formulation (sandostatin-LAR)
in patients with TSH-secreting pituitary adenomas after incomplete
surgery and octreotide treatment failure
Chun-Fang ZHANG*, Dan LIANG* and Li-Yong ZHONG*#
*
Endocrine branch, Beijing Tiantan Hospital affiliated to Capital Medical University,
Beijing, 100050, China.
# Correspondence to: Li-Yong ZHONG, Endocrine branch, Beijing Tiantan Hospital
affiliated to Capital Medical University, No. 6, Tiantanxili, Dongcheng District,
Beijing, 100050, China. E-mail: [email protected]. Tel: +86-10-67096618
Abstract
Background: To report the efficacy and safety of Sandostatin-LAR in patients with
TSH-secreting pituitary adenomas after incomplete surgery and Octreotide treatment
failure.
Methods: Fifteen patients with thyroid-stimulating hormone (TSH)-secreting
pituitary adenomas (8 male and 7 female), who previously underwent incomplete
surgical resection and/or adjuvant radiotherapy (n = 12) and failure of Octreotide
treatment (n = 15), followed between 2007 and 2010 in Beijing Tiantan Hospital were
included in this study. All patients received 1- to 2-months of Sandostatin-LAR
treatment after the above combination of treatment. Paired samples t-Test was used to
analysis the variables.
Results: After two-month duration of Sandostatin-LAR treatment, the mean serum
FT4 (16.02 ± 1.72 pM) and FT3 (2.87 ± 0.43 pM) levels of 15 patients significantly
decreased compared with those after Octreotide-treatment (FT4, 35.36 ± 7.42 pM, P <
0.001; FT3, 17.85 ± 7.22 pM, P < 0.001). Mean TSH levels stayed in the normal
range after Sandostatin-LAR treatment (0.72 ± 0.21 mU/L) and were significantly
lower than the pretreatment value (5.27 ± 1.04 mU/L, P < 0.001), post-surgery value
(3.37 ± 0.31 mU/L, P < 0.001) and post-octreotide-treatment value (4.52 ± 0.41 mU/L,
P < 0.001). In these patients with TSH-secreting pituitary adenomas there was no
evidence of tachyphylaxis.
Conclusions: Sandostatin-LAR may be a useful and safe therapeutic tool to facilitate
the medical treatment of TSH-secreting pituitary adenomas in patients who underwent
incomplete surgery or need long-term somatostatin analog therapy.
Keywords: pituitary adenomas; TSH; Sandostatin-LAR; Octreotide; surgery
Introduction
Pituitary adenomas are tumors that occur in the pituitary gland, and account for about
15%-20% of intracranial neoplasms [1]. Classification of pituitary tumors is based on
plasma hormone levels or immunohistochemical staining. Diagnosis of pituitary
adenoma can be made, or at least suspected, by a constellation of related symptoms,
and confirmed by testing hormone levels and by radiographic imaging of the pituitary.
Surgery is a common treatment for pituitary tumors. Although many pituitary tumors
are successfully resected, functional adenomas may not be cured by surgery.
Management of pituitary tumors has improved in the past decade since the
introduction of novel therapeutic agents. As a result, several treatment options are
now available. Dopamine agonists are the preferred treatment for both symptomatic
microprolactinomas
(less
than
10
mm
in
their
largest
diameter)
and
macroprolactinomas (10 mm or more); these drugs result in normalization of hormone
levels and tumor shrinkage in most treated patients. New formulations (such as
cabergoline and parenteral bromocriptine) with prolonged duration of action offer
improved compliance with treatment and cure rates [2].
Thyroid-stimulating hormone (TSH)-secreting pituitary adenomas account for less
than 1% of functioning pituitary tumors [3] and are occasionally manifested as
hyperthyroidism [4] and usually doesn't cause symptoms. However, tumor patients
with clinical manifestation of hyperthyroidism are tended to be misdiagnosed as
primary hyperthyroidism and pretreated with antithyroid drug therapy. The pituitary
tumor will increase in size after application of antithyroid drug prior to surgical
resection and it is difficult for subsequent surgery to remove the tumor completely.
Up to now, the literature contains little information about the current management of
patients with TSH-secreting pituitary adenomas or about the usefulness of the
somatostatin analogue octreotide in such cases.
In this study, we applied long-acting Octreotide formulation (Sandostatin-LAR,
Octreotide Acetate Microspheres for Injection) in patients with TSH-secreting
pituitary adenomas after incomplete surgery and failure of Octreotide treatment. Our
study demonstrated the effectiveness of treating patients with long-acting Octreotide
formulation increase the possibility of clinical remission.
METHODS
Patients
Diagnosis of TSH-secreting pituitary adenomas was based on clinical findings
(tumoral syndrome and/or thyrotoxicosis), biochemical evidence of unsuppressed
TSH levels contrasting with elevated serum thyroid hormone concentrations and the
identification of an adenoma by pituitary magnetic resonance imaging (MRI).
Additional diagnostic tools were dynamic response of TSH and a subunit (aSU) to
thyrotropin-releasing hormone (TRH), tri-iodothyronine (T3) suppression test in
questionable cases, and measurement of prolactin (PRL), growth hormone (GH),
insulin-like growth factor-I (IGF-I), luteinizing hormone (LH), follicle-stimulating
hormone (FSH) and adrenocorticotropin (ACTH) levels. All the diagnosis was
confirmed by pathology and immunohistochemistry after surgery.The tumors are
composed of choromophobic cells and exhibit sinusoidal growth pattern. By IHC, the
tumor cells are positive for TSHβ and aSU. The tumors are also sometimes
multihormonal with positive staining for GH and PRL. In this article, we follow the
guidelines and classification scheme for pituitary gland tumors that was released by
the World Health Organization (WHO) in 2004 [5].
Fifteen patients with TSH-secreting pituitary adenomas from Beijing Tiantan Hospital
affiliated to Capital Medical University between 2007 and 2010 were included in this
study (seven women and eight men; mean ± SE age, 41 ± 0.65 year). Ten patients
presented pure TSH-secreting tumors, three had a mixed TSH-GH-secreting adenoma
and two had a mixed TSH-PRL-secreting adenoma. On a computed tomography scan
or nuclear magnetic resonance imaging, three of these patients had giant adenomas
(maximal diameter > 40mm), eleven had macroadenomas (maximal diameter >
10mm), and one had microadenoma.
All patients had previously been treated with transsphenoidal incomplete surgical
resection (n = 9), transfrontal incomplete surgical resection (n = 6), and
post-surgically been treated with radiotherapy (n = 12; 45 to 50 Gy, 5 to 6 weeks) and
Octreotide (n = 15). All patients showed uncontrolled hyperthyroidism after 1 to 2
months of Octreotide treatment before this study. The individual characteristics of
each patient are summarized in Table 1.
Treatment
The present study was approved by the institutional ethics committee of the Capital
Medical University (Beijing, China), and each patient gave written informed consent.
The diagnosis of TSH-secreting pituitary adenomas was based on physical
examination, elevated free thyroid hormone concentrations in the presence of normal
or elevated TSH levels, and pituitary adenoma. After incomplete surgical resection (n
= 15) and post-surgical radiotherapy (n = 12), all patients received subcutaneous
injection (sc) of Octreotide for a period of 1 month. However, in all patients (n = 15),
TSH, T3, T4, FT3, or FT4 levels were in the abnormal range during treatment with
Octreotide (0.1 mg/8hr) for one to two months. All patients then received im
injections of Sandostatin-LAR 20 mg/month for the next two months.
Specimen collection and hormone detection
For serum TSH, T3, T4, FT3, and FT4 assay, venous blood was collected (8 am of the
day) at diagnosis, post-surgery (1 week), post-Octreotide treatment (1 or 2 month) and
Sandostatin-LAR treatment (1 and 2 months). Serum was extracted and stored at
-80℃ until further use. Hormones were measured by radioimmunoassay with kit (No,
REF 2K47-20; Abbott Laboratories, Middletown VA. USA) according to the protocol.
The reference range for T3: 0.89-2.44 nM; T4: 62.68-150.84 nM; FT3: 2.63-5.70 pM;
FT4: 9.00-19.04 pM; TSH: 0.35-4.94 mU/L.
Statistical analysis
All data were expressed as mean ± standard deviation (SD). Paired samples t-Test
(SPSS 14.0 statistical software, SPSS, Chicago, IL, USA) was used to assess the
effects of Sandostatin-LAR on T3, T4, FT3, FT4 and TSH levels in patients with
pituitary adenomas. P value of < 0.05 was considered statistically significant.
RESULTS
Clinical evaluation
All patients (n = 15) received incomplete surgical resection of the tumors after first
diagnosed as described in Table 2. Twelve patients received radiotherapy after
incomplete surgical resection. Two to three months after surgery and radiotherapy,
symptoms of hyperthyroidism recurred for all patients and treatment with 0.1mg/8hr
sc Octreotide injection were applied subsequently. However, significant symptoms of
hyperthyroidism were not effectively controlled after 1 to 2 months of Octreotide
administration. Sandostatin-LAR was used for these Octreotide treatment failure cases.
During Sandostatin-LAR administration, clinical signs improved and all patients were
euthyroid after 2 months of the i.m. Sandostatin-LAR treatment. All patients
continued monthly i.m. injections of Sandostatin-LAR after cured both clinically and
biologically.
Hormonal evaluation and treatment effects
In this cohort of 15 patients with TSH-secreting pituitary adenomas, the mean basal
serum FT4 and FT3 levels were 61.51 ± 15.33 pM (mean ± SD) and 36.76 ± 10.46
pM, respectively, before any treatment was started. One week post-surgery, the serum
FT4 and FT3 decreased to 30.22 ± 6.29 pM and 17.28 ± 5.59 pM, respectively, but 14
out of 15 cases remained abnormal (Table 3, Figure 1C, 1D). No suppression of FT4
and FT3 levels were seen in the 15 cases treated by Octreotide. Neither a tumoral
shrinkage nor an improved surgical outcome was obtained in those patients (remission
group: 0/15, failure group: 15/15). After Sandostatin-LAR treatment, mean serum
FT4 (16.02 ± 1.72 pM) and FT3 (2.87 ± 0.43 pM) levels significantly decreased
compared with those post-Octreotide-treatment (FT4, 35.36 ± 7.42 pM, P < 0.001，
Figure 1C; FT3, 17.85 ± 7.22 pM, P < 0.001; Figure 1D). Fourteen patients were
considered to be euthyroid (normal FT4 and FT3 concentrations) during the 2-month
treatment with Sandostatin-LAR. In one patient FT4 level remained abnormal at the
2-months evaluation (Figure 1D).
The mean serum TSH value at diagnosis was 5.27 ± 1.04 mU/L and fell to 4.52 ± 0.41
mU/L after two months of octreotide treatment (Table 3). After a 2-month period of
monthly im injections of Sandostatin-LAR, the mean TSH value recorded on two
months after the last injection was 0.72 ± 0.21 mU/L. Mean TSH levels stayed in the
normal range after Sandostatin-LAR treatment (0.72 ± 0.21 mU/L) and were
significantly lower than the pretreatment value (5.27 ± 1.04 mU/L, P < 0.001),
post-surgery value (3.37 ± 0.31 mU/L, P < 0.001) and post-octreotide-treatment value
(4.52 ± 0.41 mU/L, P < 0.001; Figure 1E). In these patients with TSH-secreting
pituitary adenomas there was no evidence of tachyphylaxis. The tumor sizes
decreased significantly after two months of Sandostatin-LAR (0.03 ± 0.00 cm3)
treatment compared with two months after octreotide treatment (0.62 ± 0.03 cm3) and
postsurgery (0.63 ± 0.02 cm3, P < 0.001; Figure 2).
Safety and tolerability of Sandostatin-LAR
Sandostatin-LAR is generally well tolerated by all the patients. Biochemical
examination including liver and kidney function, blood routine examination and blood
lipid and glucose concentration were taken regularly and none of the patients
expressed abnormal. Clinical manifestation including gastrointestinal disturbances
and injection site reactions were also considered. Three out of 15 (20%) patients
receiving Sandostatin-LAR experienced nausea and abdominal discomfort. One
patient (6.7%) had moderate discomfort at the injection site. Symptoms are, however,
generally mild and none of the patients require treatment withdrawal because of side
effects.
Follow-up
All patients were followed-up for a mean period of 1.87 years (range 1.2-3.0 years).
At the last follow-up examination, 13 patients fulfilled all the biochemical criteria for
remission and none had evidence of regrowth of the pituitary adenoma. The
remaining two patients are currently under long-acting Sandostatin-LAR with
acceptable biochemical control of the disease. In summary, at the last follow-up,
Hypersecretion and residual tumors were well controlled by Sandostatin-LAR
treatment in all patients after incomplete surgery and failure of Octreotide treatment.
DISCUSSION
TSH-secreting pituitary adenomas are rare, frequently are macroadenomas at
diagnosis and thus present with mass effect symptoms, together with variable
symptoms and signs of hyperthyroidism [6]. Pituitary surgery is considered the first
therapeutic approach in patients with TSH-secreting pituitary adenomas [7] to restore
euthyroidism in hyperthyroid patients and to eliminate the symptoms of mass effect in
patients with macroadenomas. Pituitary surgery led to normalization of thyroid
hormone levels and complete tumor removals in 44% of the patients, produced
normalization of thyroid hormone secretion despite incomplete tumor removals in
25% of the patients, and was unsuccessful in 29% [6, 8]. Radiation therapy, as an
adjuvant therapy, has been considered the most appropriate methods for patients not
in remission after surgery [9]. However, the percent remission of hyperthyroidism is
low after radiotherapy or stereotactic radiosurgery [4, 6].
Since somatostatin analogs [10] has been allowed to be medical treatment with
patients with TSH-dependent hyperthyroidism related to TSH-secreting pituitary
tumors, medical treatment of TSH-secreting adenomas has been widely improved [11].
Somatostatin analogs allow the control of thyroid function and tumoral mass in all
patients with TSH-secreting adenomas when surgery and/or radiotherapy have failed
[9, 12, 13]. Octreotide, a synthetic somatostatin analog with a half-life of between
80–110 min, is administered sc two or three times daily or continuously using
portable pumps. To avoid drawbacks of Octreotide such as multiple daily injections or
the use of portable pumps, Sandostatin-LAR, a long-acting octreotide formulation of
the somatostatin analog octreotide has been used. It consists of octreotide acetate
encapsulated with a biodegradable polymer (Sandostatin-LAR), and this depot
formulation is injected im every 4 weeks.
In this study, we applied used Sandostatin-LAR as a Long-Acting Octreotide
Formulation in patients with persistent TSH-dependent hyperthyroidism after
incomplete tumor removal of adenomas with/without adjuvant radiation therapy and
failure of Octreotide treatment. The first noticeable finding of our study was that in
our population of patients with TSH-secreting pituitary adenomas, who underwent
incomplete surgery and failure of Octreotide treatment, Sandostatin-LAR decreased
mean TSH, FT4, and FT3 levels in the normal range (n = 13), and long-term
treatment maintained euthyroidism in the other two patients. Postoperative
radiotherapy is generally applied after incomplete surgery. However, secreting
pituitary adenoma is moderately sensitive to radiotherapy and the efficacy needs a few
months to show up. It takes conventional radiotherapy one year or more to show
maximize therapeutic effects and ten years for patients to return to normal hormone
levels [14]. It is reported that radiotherapy decreased only 31% of the TSH levels in
patients with TSH adenoma, but cannot reduce the TSH level to normal. It is
undeniable that, in our study radiotherapy may contribute to the final treatment effect
after two months of Sandostatin-LAR administration. However, postoperative
radiotherapy alone cannot achieve cure rate of 87% within 5-6 months.
The second important finding in this series was that Sandostatin-LAR was well
tolerated throughout the study. Minor digestive problems (nausea, mild abdominal
pain, and softened stools) or moderate discomfort at the injection site, lasting less than
48 h, were reported by three and one patients, respectively, and did not require
interruption of the treatment. In this study, gallbladder echographies did not reveal the
occurrence of gallstones in any patient during Sandostatin-LAR treatment as also
reported by Kuhn et al. [15]. On the other hand, after two-month treatment with
multiple daily s.c. injections of Octreotide, the patients noted the convenience of
monthly injections and continued i.m. Sandostatin-LAR at the end of the study.
In conclusion, this study shows the efficacy and safety of Sandostatin-LAR in patients
with TSH-secreting pituitary adenomas that were responsive to Sandostatin-LAR,
who were previously treated with incomplete surgery and/or pituitary radiotherapy
and failure of Octreotide treatment. Sandostatin-LAR may be a useful and safe
therapeutic tool to facilitate the medical treatment of TSH-secreting pituitary tumors
in patients who underwent incomplete surgery or need long-term somatostatin analog
therapy.
Authors’ disclosures of potential conflicts of interest
The authors indicated no potential conflicts of interest.
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Table 1. Clinical characteristics of the 15 patients with a TSH-secreting pituitary
adenoma at first diagnosis
At first diagnosis
Patient
Age
Follow
no.
(yr)
Tumor size
TSH
Sex
up (yr)
T3 (nM)
T4 (nM)
FT3 (pM)
FT4 (pM)
(0.89-2.44)
(62.68-150.84)
(2.63-5.70)
(9.00-19.04)
(mm3)
(mU/L)
(0.350-4.94)
1
38
M
1.5
4.59
12.29
308.88
> 46.08
> 77.22
3.0 × 2.8 × 3.1
2
45
F
2.0
4.46
8.12
> 308.88
20.25
45.53
2.2 × 2.0 × 3.0
3
46
M
1.7
8.44
2.66
141.46
5.45
15.94
1.6 × 2.0 × 2.1
4
42
M
2.2
4.66
11.26
288.76
42.08
71.12
3.5 × 2.9 × 3.2
5
33
F
1.2
4.37
9.37
288.76
38.33
58.32
1.0 × 1.6 × 1.2
6
26
F
1.5
5.44
10.37
268.04
41.22
62.33
2.5 × 2.6 × 3.1
7
33
M
2.0
5.59
11.28
287.78
42.09
76.22
4.3 × 3.8 × 3.1
8
44
F
2.5
4.69
9.79
274.18
39.67
66.22
2.4 × 3.0 × 3.2
9
32
M
2.3
6.68
12.38
309.77
45.18
76.12
2.6 × 3.2 × 3.0
10
48
F
1.2
5.19
9.19
268.77
41.18
68.34
3.5 × 3.2 × 3.6
11
37
M
1.6
5.00
8.87
288.56
39.17
57.22
5.2 × 4.7 × 5.0
12
42
F
1.5
4.87
10.28
297.76
39.07
67.12
2.4 × 2.7 × 3.2
13
49
M
1.7
5.01
8.97
267.66
36.06
57.21
3.1 × 2.6 × 2.7
14
51
F
2.1
5.24
9.05
288.76
37.18
66.32
5.5 × 5.0 × 8.0
15
37
M
3.0
4.88
8.64
256.67
38.36
57.46
1.8 × 2.1 × 2.6
FT3, free T3; FT4, free T4.
Table 2. Treatments of the 15 patients with a TSH-secreting pituitary adenoma
Treatment
Patient
Pathological
Primary
no.
Sandostatin
Radiotherapy
Octreotide#
staining
LAR*
treatment
1
TSS
+
0.1mg, 2months
20mg, 2 months
TSH
2
TSS
－
0.1mg, 1months
20mg, 2 months
TSH
3
TSS
+
0.1mg, 1months
20mg, 2 months
TSH
4
TFS
+
0.1mg, 1months
20mg, 2 months
TSH
5
TSS
－
0.1mg, 1months
20mg, 2 months
TSH
6
TSS
+
0.1mg, 1months
20mg, 2 months
TSH+GH
7
TFS
+
0.1mg, 1months
20mg, 2 months
TSH+GH
8
TSS
+
0.1mg, 1months
20mg, 2 months
TSH
9
TFS
－
0.1mg, 2months
20mg, 2 months
TSH+GH
10
TFS
+
0.1mg, 1months
20mg, 2 months
TSH+PRL
11
TFS
+
0.1mg, 1months
20mg, 2 months
TSH
12
TSS
+
0.1mg, 1months
20mg, 2 months
TSH
13
TSS
+
0.1mg, 1months
20mg, 2 months
TSH
14
TFS
+
0.1mg, 1months
20mg, 2 months
TSH+PRL
15
TSS
+
0.1mg, 1months
20mg, 2 months
TSH
TSS, transsphenoidal surgery; TFS, transfrontal surgery; TSH, thyroid-stimulating hormone; GH,
growth hormone; PRL, prolactin; #Dose of every 8 hours, duration of Octreotide treatment.
*Monthly dose, duration of Sandostatin-LAR treatment. Five to six weeks of treatment of
radiotherapy (45-50Gy).
Table 3. Serum hormones before and after treatments
Hormonal
At first
1 week
evaluation
diagnosis
postsurgery
TSH (mU/L)
5.27 ± 1.04
3.37 ± 0.31
Octreotide
Sandostatin-LAR
Normal range
T3 (nM)
9.50 ± 2.30
1 month
2 months
1 month
2 months
1.67 ±
4.52 ±
1.02 ±
0.72 ±
0.82
0.41
0.43
0.21
2.42 ±
6.29 ±
1.53 ±
1.08±
0.69
1.57
0.44
0.30
0.35-4.94
4.64 ± 0.87
0.89-2.44
275.65 ±
216.38 ±
185.96 ±
233.19 ±
128.19 ±
111.87 ±
43.11
36.99
38.38
46.02
37.37
17.97
36.76 ±
17.28 ±
3.90 ±
17.85 ±
3.40 ±
2.87 ±
10.46
5.59
1.07
7.22
0.63
0.43
61.51 ±
30.22 ±
23.35 ±
35.36 ±
18.83 ±
16.02 ±
15.33
6.29
4.11
7.42
3.31
1.72
T4 (nM)
62.68-150.84
FT3 (pM)
2.63-5.70
FT4 (pM)
9.00-19.04
All data, Mean ± SD.
Figures and figure legends
Figure 1. Changes in serum T3 (A), T4 (B), FT4 (C), FT3 (D) and TSH (E)
concentrations in 15 patients with TSH-secreting pituitary adenoma at diagnosis,
one-week after surgery, after octreotide and Sandostatin-LAR treatments. The red line
with red spot indicates the mean of the hormone in 15 patients.
Figure 2. Treatment effects of Sandostatin-LAR. (A) Coronal (a, c) and sagittal (b, d)
magnetic resonance imaging (MRI) in patient 1 displaying a tumor mass before
treatment with surgery (a, b) and after treatment with surgery (c, d). (B) Comparison
of tumor sizes of 15 patients with TSH-secreting pituitary adenoma at diagnosis, after
surgery, after octreotide treatment and Sandostatin-LAR treatment. The red line
indicates the mean of the 15 tumor sizes. Tumor sizes decreased significantly two
months after Sandostatin-LAR treatment compared with two months after octreotide
treatment and postsurgery. Number 1 to 15 indicates patient 1 to 15.