Full text of DOI:10.1007/BF03345511

J. Endocrinol. Invest. 25: 773-778, 2002
Somatostatin analogs in the treatment of medullary thyroid
carcinoma
J.J. Díez* and P. Iglesias**
*Department of Endocrinology, Hospital La Paz, Madrid, and **Department of Endocrinology, Hospital
General de Segovia, Segovia, Spain
ABSTRACT. The medical therapy for advanced or
metastatic medullary thyroid carcinoma has not
been fully established. Somatostatin analogs have
been used with variable success in the therapy of
a few patients with medullary thyroid carcinoma.
In the present study, we evaluated the effects of
somatostatin analog therapy on calcitonin (ct) and
carcinoembryonic antigen in patients with ad-
vanced medullary thyroid carcinoma. Five pa-
tients (2 men and 3 women, aged 35-57 yr) with
post-operative recurrent medullary thyroid carci-
noma received somatostatin analog therapy for
12 weeks. All had been previously treated with
total thyroidectomy and lymphadenectomy. Four
of them showed positive uptake in 111In-pente-
treotide scanning. One patient was treated with
sc octreotide (100 μg/8 h), 3 patients received im
slow release lanreotide (30 mg/14 days), and a
further one received im octreotide LAR (30
mg/28 days). Serum samples for ct and carci-
noembryonic antigen were obtained at 0, 1, 2, 4,
8 and 12 weeks of therapy. Therapy was well-tol-
erated in general, with minimal side-effects. One
patient died after the first month of therapy be-
cause of advanced disease. Another patient show-
ed normalization of his ct and carcinoembryonic
antigen concentrations at the second week of
therapy, maintaining elevated values thereafter.
No clinically relevant changes in serum concen-
trations of ct and carcinoembryonic antigen were
observed in the rest of the patients. One patient
with positive 111In-pentetreotide scan, showed no
uptake after somatostatin analog therapy. No sig-
nificant decrease in the size of metastases was
evident in the remaining patients. In conclusion,
therapy with different formulations of octreotide
and lanreotide does not seem to modify serum
concentrations of ct and carcinoembryonic anti-
gen in patients with recurrent medullary thyroid
carcinoma.
(J. Endocrinol. Invest. 25: 773-778, 2002)
©2002, Editrice Kurtis
INTRODUCTION
volved nodes (1, 2). Post-operative high serum
concentrations of tumor markers, ct and CEA, sug-
gest persistence or recurrence of the disease.
Recurrences are usually evaluated by US, CT and
scanning with radiotracers such as 123I-metaio-
dobenzylguanidine (MIBG). The medical treatment
of recurrences and that of advanced or metastat-
ic disease has not been well established. Re-
peated surgery is indicated in cases of disease re-
currence with compromise of structures in the
neck. Radiotherapy and chemotherapy have also
been suggested, although results seem to be of
little benefit (2).
Therapy with somatostatin analogs (SSA) has be-
come a new therapeutic approach in patients with
MTC with the rationale that these tumors may ex-
press somatostatin receptors (3). Octreotide and
lanreotide, the available somatostatin analogs for
clinical use, have shown to be safe and effective
treatments for GH-secreting pituitary adenomas,
Medullary thyroid carcinoma (MTC) is derived from
the parafollicular cells (C cells) of the thyroid and
accounts for as many as 10% of all thyroid malig-
nancies. Tumor C cells release calcitonin (ct), carci-
noembryonic antigen (CEA) and several other pep-
tides. The majority of MTC are sporadic, with a 20%
inherited as an autosomal dominant form. Tumors
are multifocal in 20% of sporadic cases and 90% of
familial. Metastases usually occur in lymph nodes
of the neck and mediastinum, but may also be
found in the lung, bone and liver (1).
Therapy for MTC requires total thyroidectomy and
removal of the central lymph nodes and all in-
Key words: Octreotide, lanreotide, medullary thyroid carcinoma.
Correspondence: Dr. Juan J. Díez, Travesía Téllez 8, 4R 28007 Madrid. Spain.
E-mail: mibarsd@infomed.es
Accepted May 21, 2002.
773

Somatostatin in MTC
Table 1 - Clinical characteristics of studied patients.
#
1
2
Sex, age
(yr)
Mutation
Clinical presentation
Previous therapy
Metastases at diagnosis Duration of
disease (yr)
M, 35
Exon 11,
TCG(634)TAG
Thyroid nodule, palpable
lymph nodes in the neck
Surgery (1)
Radioiodine (80 mCi)
Cervical lymph nodes
1
M, 38
None
Nodular goiter
Surgery (3)
Radioiodine (100 mCi)
External radiotherapy
Unknown
12
3
4
5
F, 57
F, 44
F, 45
None
None
Nodular goiter, palpable
lymph nodes in the neck
Surgery (2)
Cervical lymph nodes
2
0.5
1
Nodular goiter, palpable
lymph nodes in the neck
Surgery (3)
Radioiodine (130 mCi)
Cervical and subman dibular
lymph nodes
Exon 15,
TCG(891)GCG
Nodular goiter, palpable
lymph nodes in the neck
Surgery (1)
Radioiodine (100 mCi)
External radiotherapy
Cervical and supra-clavicular
lymph nodes
M=male; F=female.
ly with total thyroidectomy in combination with lymphonodal
dissection as primary therapy of their disease. Radioiodine ther-
apy was employed in 4 of them, and external radiotherapy was
used as adjunctive therapy in 2 cases. Surgical excision of re-
currences was performed in 3. All patients were on replacement
doses of LT4 and were euthyroid.
All patients showed high serum concentrations of both ct (112-
2158 pg/ml) and CEA (29.8-194.9 ng/ml), thus indicating the
persistence of malignant parafollicular tissue (Table 2). Total
body CT revealed metastases in 2 patients (number 2 and 4),
whereas scintigraphy with 123I-MIBG showed pathological up-
take in one case (number 2). Four patients showed in vivo so-
matostatin receptors, as visualized after iv administration of 111In-
diethylenetriamine-pentacetic acid-D-Phe1-octreotide (pente-
treotide) (Table 2).
carcinoid tumors, as well as some other neuroen-
docrine tumors with somatostatin receptors (4).
Several authors have reported on the effectiveness
of octreotide (5-8) or the combination of SSA with
interferon (9, 10) in patients with MTC. Results have
been variable, with clinical improvement in many
cases, although no evidence of reduction of metas-
tases or tumor mass has been reported so far. In
the present study, we evaluated the effects of dif-
ferent formulations of SSA, octreotide and lan-
reotide, on serum concentrations of ct and CEA in
5 patients with post-operative recurrent MTC.
All patients gave written informed consent before starting ther-
apy with SSA. One patient (number 1) was treated by sc admin-
istered octreotide, 100 μg/8 h, three patients (number 2-4) were
given im injections of slow release lanreotide, 30 mg every 14
days, and a further patient (number 5) was treated with oc-
treotide LAR, 30 mg every 28 days, by im route. Duration of
therapy with SSA was 12 weeks. They were evaluated at month-
ly intervals for registering clinical evolution and adverse effects.
Baseline blood samples were drawn before starting therapy with
SUBJECTS AND METHODS
We studied 5 patients (2 men and 3 women, Table 1) ranging in
age from 35-57 yr (mean SD, 44 8 yr), with histologically
proven MTC and with post-operative recurrence of the disease
as demonstrated by elevated serum levels of ct and CEA. Three
patients had sporadic MTC and 2 had the familial form of MTC.
None had clinical or laboratory evidence of hyperparathyroidism
or pheochromocytoma. All patients had been treated previous-
Table 2 - Biochemical and imaging techniques results of the studied patients before starting somatostatin analog therapy.
#
ct
(pg/ml)
CEA
(ng/ml)
CT
123I-MIBG scintigraphy
111In-pentetreotide scintigraphy
1
2
358
17.3
No metastases
Negative
Not done
2158
175.5
Local recurrence,
metastases in
dorsal column
Positive uptake in
mediastinum and
dorsal column
Positive uptake in dorsal column
3
4
1365
891
53.7
No metastases
Negative
Negative
Positive uptake in neck and mediastinum
194.9
Cervical lymph nodes
Positive uptake in dorsal column,
sacroiliac joint, femur and iliac crest
5
112
29.8
No metastases
Negative
Positive uptake in sternoclavicular joint
CEA: carcinoembryonic antigen; MIBG: metaiodobenzylguanidine.
774

J.J. Díez and P. Iglesias
A
2000
1500
1000
500
SSA and at 1, 2, 4, 8 and 12 weeks for determination of ct and
CEA. In these samples we also assessed complete blood cell
count, and serum concentrations of glucose, creatinine, choles-
terol, triglyceride, calcium, phosphorus, total protein, aspartate
aminotransferase, alanine aminotransferase, ALP, and lactic de-
hydrogenase, TSH and free T4. Total body CT and scintigraphy
with 111In-pentetreotide were repeated 1-3 months after finish-
ing therapy with SSA.
Serum ct concentrations were determined by using an IRMA as-
say (BioSource Europe, Nivelles, Belgium). Maximal intra- and
inter-assay coefficients of variation were 3.4% and 5.4%, re-
spectively. The sensitivity of the assay was 0.8 pg/ml. ct con-
centrations in healthy people without hyperplasia of C cells or
MTC were less than 10 pg/ml. CEA levels were measured by us-
ing an enzymoimmunoassay (AxSYM CEA, Abbott, Wiesbaden,
Germany). The normal concentration for healthy subjects was
less than 5 ng/ml. Maximal intra- and inter-assay coefficients of
variation were 7.0% and 6.9%, respectively. The sensitivity of
the assay was 0.5 ng/ml.
0
B
400
Patient 1
Patient 2
Patient 3
Patient 4
Patient 5
300
200
100
0
RESULTS
0
2
4
8
12
Three patients (number 2, 3 and 5), who were
asymptomatic at the start of the study, did not re-
port any clinical change in their general state.
Patient 1 complained of impairment of his pre-ex-
isting diarrhea at the third month of therapy. Patient
4, who had multiple bone metastases at the start
of the study, suffered a dramatic impairment of her
general condition and lastly died after the first
month of the study. SSA therapy was in general well
tolerated. Diarrhea and loose stools were reported
by patients (number 1 and 2). Patient number 3 re-
ported a 2-day duration fever episode after the
fourth injection of lanreotide. Patient number 5
complained of transitory local pain at the site of in-
jection of octreotide LAR.
Time (weeks)
Fig. 1 - Evolution of individual values of serum concentrations
of ct (A) and carcinoembryonic antigen (B) in 5 patients with
medullary thyroid carcinoma treated with somatostatin analogs
for 12 weeks (sc octreotide in patient 1, im slow release lan-
reotide in patients 2-4, and im octreotide LAR in patient 5).
CEA: carcinoembryonic antigen; ct: calcitonin.
In patient 2, who have residual tumor in the neck
and bone metastases, second examination also
showed lung nodules and lymph nodes in the me-
diastinum. Patient 3, who had no lesions before
starting the study, showed local recurrence with
lymph nodes in the neck. 111In-pentetreotide scin-
tigraphy performed after the study period was
positive in patients 2 and 3, and negative in pa-
tient 1. Patient 5, who had a positive uptake in the
first examination, was negative on this second oc-
casion.
Individual values of serum concentrations of ct and
CEA are shown in Figure 1. Patient number 2 ex-
hibit a dramatic fall in tumor markers at week 2,
reaching normal values for serum concentrations of
both ct (1.6 pg/ml) and CEA (1.9 ng/ml). However,
these values returned to high levels at weeks 4 to
12. The remaining patients did not show any clini-
cally relevant change in their values of both ct and
CEA. After 12 weeks, the percentages of serum ct
levels variation in patients 1, 2, 3 and 5 were, re-
spectively, +25.1%, -14.3%, -22.4% and +4.1%
from the initial levels. Values of percent variation
for CEA concentrations in the same patients were
-21.5%, -47.8%, +47.3% and +2.4%, respectively.
We did not observe any significant variation of
hematological and biochemical tests throughout
the study period. Thyroid function tests also re-
mained unchanged.
DISCUSSION
All studied patients showed elevated serum levels
of tumor markers and 4 of them had evidence of
metastases in imaging techniques. No significant
change in clinical state was recorded in 3 asymp-
tomatic patients (2, 3 and 5). Patient 1 reported an
impairment of his diarrhea in the third month of
therapy. Patient 4, with advanced disease at the
start of the study, progressively impairs and died.
Our results clearly show that SSA therapy for 3
months does not modify serum concentration of ct
Post-therapy CT was negative in patients 1 and 5.
775

Somatostatin in MTC
and CEA in patients with recurrent MTC. We only
observed a frank decline with normalization of both
tumor markers in one patient treated with lan-
reotide, but this effect was transitory. We have no
clear explanation for this finding, but a similar phe-
nomenon was observed in 1 of the patients studied
by Lupoli et al. (9) after 3 months of therapy with
octreotide in combination with interferon.
A number of investigators have been interested
in the use of SSA in the treatment of advanced
MTC (Table 3). Most of them reported an im-
provement in symptoms (5, 7, 11, 14-16, 19, 20,
22, 25, 27, 28), whereas others did not observe
any significant clinical improvement (12, 21). The
effects of octreotide therapy on ct concentration
have been variable and contradictory (Table 3).
Reduction of ct levels below 50% of basal values
have been reported in isolated patients (8,19).
Guliana et al. (6) reported a decrease in ct levels in
10 out of 18 patients treated with octreotide, how-
ever, only 5 of these patients show a decrement of
20% or more. In many cases, octreotide adminis-
tration appears to have no effect on ct levels in
both acute administration (6, 22, 29) and chronic
therapy (11, 12, 14-16, 22, 23). Other investiga-
tors have found a decrease of ct levels in some
patients and an increase in other patients under
the same protocol (5, 6, 20, 21, 24, 28). In some
occasions, an initial decrease in ct levels followed
by a subsequent rise has been reported (13, 19,
27). CEA concentrations have been found to be
unmodified by octreotide therapy (5, 20, 21, 24).
The high variability of results may be accounted for
the wide range of doses of octreotide, the differ-
ent duration of therapy and the diverse disease
staging of the patients. A decrease in ct levels
Table 3 - Reported results on the effects of somatostatin analogue therapy on serum ct concentrations in patients with medullary thy-
roid carcinoma.
Author and year
Num.
of patients
Dose (μg/day)*
Duration
(months)
Changes in
ct levels
Changes in
measurable lesions
Geelhoed et al., 1986 (11)
Schrezenmeir et al., 1986 (12)
Berkelhammer et al., 1986 (13)
Alhman et al., 1987 (14)
Jerkins et al., 1987 (15)
Keeling et al., 1988 (16)
Modigliani et al., 1989 (5)
Guliana et al., 1989 (6)
Sagman et al., 1989 (17)
Libroia et al., 1989 (7)
1
3
200-500
100-150
100-1500
100-200
50-100
100
3
5 days
1
No change
No change
Dec & Inc
No change
No change
Inc
No change
Ns.
1
Ns.
1
3
Ns.
1
7
No change
1
N.E.
1-2
1-2
3
Inc
18
18
2
300-1500
300-1500
200
Dec 11, Inc 7
Dec 10, Inc 8
No change
Dec 1
Dec 5
Ns.
Ns.
2
300
3
Ns.
Libroia et al., 1990 (8)
2
200-300
300
1-3
6
Dec 2
Ns.
Somlo et al., 1990 (18)
Mahler et al., 1990 (19)
Fugazzola et al., 1991 (20)
Modigliani et al., 1992 (21)
Smid et al., 1992 (22)
1
No change
Dec & Inc
Dec 1, Inc 2
Dec 4, Inc 7
No change
No change
Dec 1, Inc 5
Dec 2
Ns.
3
600-2000
150-900
500
3-17
0.5-7
3
Ns.
5
Inc 2
14
1
No change 7, Dec 1, Inc 6
300
12
1-8
3-9
3-9
3-9
6
Inc
Inc 3
Kvols et al., 1992 (23)
3
1500
Frank-Raue et al., 1993 (24)
Frank-Raue et al., 1995 (25)
Ronga et al., 1995 (26)
Sanabria et al., 1995 (27)
Di Bartolomeo et al., 1996 (28)
Lupoli et al., 1996 (9)
6
200-1000
300-600
300-600
300-500
1500-3000
150-300**
***
No change 3, Inc 3
Dec 1
7
5
Dec
Dec 3
1
Dec & Inc
Dec & Inc
Dec 6
Inc
12
6
5
No change 4, Inc 8
No change
No change 3, Dec 2, Inc 2
12
12
Vitale et al., 2000 (10)
7
Dec 6, Inc 1
Dec: decrease in ct levels or in lesion size; Inc: increase in ct levels or in lesion size; N.E.: not established; Ns.: not studied. *All doses refer to sc octreotide.
**In combination with interferon α-2b. ***Lanreotide (30 mg/10-14 days), in combination with interferon α-2b.
776

J.J. Díez and P. Iglesias
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778