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The Journal of Clinical Endocrinology & Metabolism 91(4):13971403

Copyright 2006 by The Endocrine Society
doi: 10.1210/jc.2005-2347

Primary Treatment of Acromegaly with Octreotide LAR:

A Long-Term (Up to Nine Years) Prospective Study of Its
Efficacy in the Control of Disease Activity and
Tumor Shrinkage
Renato Cozzi, Marcella Montini, Roberto Attanasio, Mascia Albizzi, Giovanni Lasio, Sandro Lodrini,
Paola Doneda, Liana Cortesi, and Giorgio Pagani
Divisions of Endocrinology (R.C., R.A.) and Neuroradiology (P.D.), Ospedale Niguarda, I-20162 Milan, Italy; Department of
Neurosurgery (G.L., S.L.), Neurological Institute Carlo Besta, I-20133 Milan, Italy; and Division of Endocrinology (R.A.,
M.M., M.A., L.C., G.P.), Ospedali Riuniti, I-24100 Bergamo, Italy
Context: Neurosurgery is regarded as the first-line treatment of
acromegaly. Because of its low cure rate in macro and invasive adenoma, the role of primary medical treatment is debated.
Objective: Our objective was to evaluate primary pharmacological
treatment in acromegaly.
Design and Setting: We conducted an open prospective study at two
Italian tertiary level centers.
Patients: We studied 67 consecutive patients (36 women; age, 54.9
14.2 yr; 72% bearing macroadenoma).
Intervention: Individually tailored octreotide LAR (OCLAR) was
administered.
Main Outcome Measures: Outcomes included safe GH (2.5 g/
liter), normal age-matched IGF-I levels, and tumor shrinkage.

months), safe GH levels and normal age-matched IGF-I values were

obtained by 68.7 and 70.1% of patients, respectively. Hormonal endpoints were achieved regardless of basal levels, and early results were
predictive of outcome. Tumor shrank in 82.1% of patients by 62 31%
(range, 0 100%), decreasing from 2101 2912 to 1010 2196 mm3
(P 0.0001). The higher the basal GH values and the greater the
GH/IGF-I changes on treatment, the greater the tumor shrinkage.
Tumor disappeared in three patients and was progressively reduced
to empty sella in five patients; apparent magnetic resonance imaging
cavernous sinus invasion disappeared in three. In males, testosterone
increased, restoring eugonadism in 64% of hypogonadal patients.
Conclusions: The efficacy on GH/IGF-I levels in unselected patients
and the outstanding volumetric control indicate that treatment with
OCLAR may be the first therapeutic approach to all acromegalic
patients not amenable to surgical cure. Tumor shrinkage might also
encourage the evaluation of primary OCLAR adoption in patients
with initial visual field defects. (J Clin Endocrinol Metab 91:
13971403, 2006)

Results: After a median follow-up of 48 months (range, 6 108

CROMEGALY IS A chronic disfiguring disease that

impairs life expectancy and quality of life (13). Increased mortality rate is reverted to that of the normal population after decreasing GH and IGF-I levels to less than 22.5
g/liter and normal sex- and age-matched controls, respectively, regardless of the treatment employed (4 9). According to guidelines and consensus, the first-line treatment is a
neurosurgical procedure (10). Its outcome depends on adenoma size, basal GH levels, and the neurosurgeons expertise
(11, 12). Adenoma size and basal GH levels are inversely
correlated to neurosurgical outcome. In the best surgical
series, the cure rate ranges between 80 and 90% in microadenoma, near 50% in macroadenoma, and far less if the adenoma is invasive (12). On the other hand, the results of
First Published Online January 31, 2006
Abbreviations: CV, Coefficient of variation; HbA1c, glycated hemoglobin; MRI, magnetic resonance imaging; OCLAR, octreotide LAR;
OGTT, oral glucose tolerance test; PT, primary treatment; SA, somatostatin analogs.
JCEM is published monthly by The Endocrine Society (http://www.
endo-society.org), the foremost professional society serving the endocrine community.

medical therapy were improved consistently using depot

somatostatin analogs (SA). Many studies have convincingly
shown their efficacy on hormonal levels and tumor size (13).
These drugs, formerly used as adjuvant treatment only, are
widely used also as primary treatment (PT) today (10, 14).
However, the ideal PT of acromegaly is still controversial.
We evaluated prospectively the effects of primary octreotide LAR (OCLAR) treatment on GH/IGF-I hypersecretion and tumor size in 67 consecutive naive acromegalic
patients, mainly with macroadenoma.
Patients and Methods
Patients
Inclusion criteria were as follows: consecutive patients with active
acromegaly, according to clinical picture, elevated GH levels not suppressible below 1 g/liter after oral glucose tolerance test (OGTT), and
high age-adjusted IGF-I levels; macroadenoma or invasive microadenoma at magnetic resonance imaging (MRI) scans; and no previous
neurosurgery or radiotherapy.
Exclusion criteria were as follows: intrasellar microadenoma (except
in patients refusing or unable to undergo neurosurgery); ophthalmological or neurological involvement; and liver or renal disease.
Sixty-seven consecutive naive acromegalic patients entered this pro-

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1398

J Clin Endocrinol Metab, April 2006, 91(4):13971403

spective open study between January 1996 and December 2004. Demographic and clinical data are depicted in Table 1.
For patients with hypopituitarism, substitutive treatment with l-T4
and cortisone acetate was regularly started as needed.
Each patient gave informed consent after full explanation of the
purpose of the study, and the procedures followed were in accordance
with the Helsinki Declaration of 1975 as revised in 1983.

Protocol
The endpoints were the achievement of safe GH levels (2.5 g/liter)
and normal age-matched IGF-I, in agreement with consensus guidelines
(15), and tumor shrinkage, as defined below.
After the baseline evaluation, OCLAR was started at the dose of 20
mg administered im every 28 d. The drug dosage was then individualized at 3- to 6-month intervals; it was escalated to 30 mg if GH or IGF-I
levels remained pathological or decreased to 10 mg if IGF-I levels fell to
less than 50% of the upper limit of the normal range.
Dopamine agonist administration was not allowed throughout the
study.
Patients not reaching hormonal targets within 12 months were offered
alternative treatments (neurosurgery or lanreotide or dopamine agonist
addition). Those accepting alternative treatment were dropped from the
study (and values obtained at that time were regarded as the last follow-up evaluation).
Testosterone or estroprogestinic replacement treatment was not administered to hypogonadal patients in the first 6 12 months to allow the
evaluation of treatment-induced recovery from hypogonadism.
Patients were checked at regular intervals (3 6 months during the
first year and yearly thereafter). Clinical (addressing menstrual history
in premenopausal females and scoring in all patients headache, perspiration, swelling, arthralgia, and fatigue) and biochemical evaluations of
hormonal, metabolic, and safety parameters were performed on an
outpatient basis before the start of treatment and at every follow-up visit.
Ophthalmological evaluation (in patients bearing macroadenoma) and
MRI were performed before the start of treatment, at 6 and 12 months,
and yearly thereafter. Ultrasound abdominal scan was performed before
the start of treatment, and at 12- to 24-month intervals thereafter.
Blood samples were collected in the morning hourly for at least 3 h
after an overnight fast and rest, while the patients were supine and
awake, with an indwelling needle inserted in an antecubital vein, kept
patent by slow infusion of saline. GH concentrations were assayed on
each sample (the value reported is the mean of all samples); IGF-I, other
hormones, and metabolic and safety parameters were assayed on the
first sample.

Methods
Serum GH levels were measured by immunometric assay (Diagnostic
Products Corp., Los Angeles, CA) with standards calibrated against
World Health Organization First International Standard 80/505 (1 g/
liter 2.6 mU/liter). The sensitivity is 0.01 g/liter, the intra- and
interassay coefficients of variation (CV) are 2.9 4.6 and 4.2 6.6%,
respectively.
Serum IGF-I was measured after acid-ethanol extraction by a chemiTABLE 1. Demographic and clinical data
Sex (male/female)
Age (yr)
Hyperprolactinemia
Diabetes
Hypopituitarism (thyroid, adrenal, gonad)
Microadenoma (invasive %)
Macroadenoma (invasive %)
Invasive adenoma (%)

Cozzi et al. Primary Medical Therapy of Tumor in Acromegaly

luminescence assay (Nichols Institute Diagnostics, San Juan Capistrano,

CA). The calibration with regard to the World Health Organization
International Standard, National Institute for Biological Standards and
Control 87/518, yields a conversion factor of 1.66. The intra- and interassay CV are 3.7 and 7.2%, respectively. Normal values for IGF-I are
182780, 114 492, 90 360, and 71290 g/liter in patients aged 16 24,
2539, 40 54 yr, and older than 55 yr, respectively.
Total testosterone was assayed by chemiluminescence (Roche, Milan,
Italy), with intra- and interassay CV of 1.1 4.6 and 1.77.4%, respectively, and normal values ranging from 2.8 11 g/liter.
Serum levels of prolactin, free T4, and urinary free cortisol (after
extraction), glucose (fasting and at 120 min after OGTT), glycated hemoglobin (HbA1c), cholesterol (total as well as high-density lipoprotein
and low-density lipoprotein), triglycerides, and safety parameters
(blood count, liver, and kidney tests) were assayed by commercial
methods.
Ophthalmological evaluation was performed by Goldmann or computerized perimetry and visual acuity testing.
MRI was performed by Philips Gyroscan (Philips, Eindhoven, The
Netherlands) (ACS-NT) 1.5 T. A neuroradiologist unaware of the ongoing treatment blindly evaluated the images. For the purpose of this
study, all images of a patient were reevaluated in a single session. On
each scan, the largest diameter of the tumor was measured on coronal
(vertical diameter and transverse) and sagittal (anteroposterior) sections. After correction for magnification factor, the approximate volume
of the adenoma was calculated as the volume of a rotating ellipsoid, with
the formula previously described (16): volume (vertical diameter
anteroposterior transverse)/6. The shrinkage of the tumor was arbitrarily considered significant when its volume was reduced by at least
25%.

Statistical analysis
Values are expressed as mean sd, unless otherwise stated.
Analyses were performed by GB-Stat 6.5.4 PPC.
Data were analyzed by parametric or nonparametric tests, depending, respectively, on whether or not they passed preliminary
Kolmogorov-Smirnov test for normality. Continuous variables with normal distribution were analyzed by t test for paired or unpaired data,
completely randomized ANOVA followed by Newman-Keuls test,
ANOVA for repeated measures followed by Dunn test, and Pearson
correlation test. Continuous variables with uneven distribution were
analyzed by Wilcoxon test, Mann-Whitney test, Kruskall-Wallis test, and
Spearman correlation test. Multiple regression analysis and logistic regression analysis were performed only on data that were significantly
correlated in pairwise analysis. Categorical variables were analyzed by
2 test or Fisher exact test, as appropriate. Longitudinal evaluations were
performed by Kaplan-Meier method, and differences between subgroups were evaluated by log-rank test.
To evaluate the predictivity of basal levels and early results on final
outcome at multiple levels without the bias of predetermined criteria, we
constructed receiver operating characteristic curves by plotting the sensitivity against (1 specificity) at each level using dedicated software.
All statistical tests were two-tailed, and values of P 0.05 were
considered significant.

Results
31/36
54.9 14.2
10
16
17 (3, 0, 13)
19 (60%)
48 (42%)
31 (46%)

For invasive adenoma, invasion was operatively defined at neuroradiological imaging as the spreading of the adenoma, both marked
and apparent, into the cavernous or sphenoidal sinus (27 and four
patients, respectively). Eight patients without a clear distinction between the adenoma and the medial wall of cavernous sinus and/or the
floor of pituitary fossa were attributed to this category.

Patients were followed up for a median period of 48

months (range, 6 108 months). Of the 67 patients entering
the protocol, 34 stayed on OCLAR (32 with normal and two
with only mildly elevated GH and IGF-I levels). The other 33
patients elected to switch to alternative forms of therapy
(surgery, lanreotide, or addition of cabergoline) within 6 84
months of OCLAR therapy even though in 23 of them either
GH or IGF-I concentrations became normal on OCLAR (in
six, both GH and IGF-I). At baseline, demographic, clinical,
and hormonal parameters were not different between patients who dropped OCLAR later and the ones who did not
(data not shown).

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Cozzi et al. Primary Medical Therapy of Tumor in Acromegaly

J Clin Endocrinol Metab, April 2006, 91(4):13971403

1399

At the last follow-up evaluation, six (9%), 10 (14.9%), and

44 (65.7%) patients were treated with 10, 20, and 30 mg every
28 d, respectively.
Clinical score improved in all responsive patients (data not
shown).
GH/IGF-I levels

GH fell from 29.3 27.8 to 3.2 4.7 g/liter at the last

follow-up evaluation (P 0.0001), reaching levels less than
2.5 g/liter in 46 patients (68.7%). IGF-I decreased from
886 332 to 329 210 g/liter (P 0.0001) (274 119 and
99 63% of the upper limit of the normal range, respectively), reaching normal levels in 47 patients (70.1%). The
percentage decreases were 81.5 21.7% (median, 90%;
range, 0 99%), and 59 27% (median, 66%; range, 29 to
90%) for GH and IGF-I, respectively.
Both safe GH and normal IGF-I levels were achieved in 38
patients (56.7%). In the patients not achieving hormonal targets, GH and IGF-I decreased by 64 28% (median, 70%;
range, 0 97%) and 31 29% (median, 33%; range, 29 to
74%), respectively.
Three patients (4.5%) were quite unresponsive to treatment (arbitrarily defined as a less than 10% change in GH/
IGF-I levels within 6 months).
GH/IGF-I decreased mostly within 6 12 months, IGF-I
levels further decreased (P 0.01 for last time points vs. 6
months), and the number of patients achieving hormonal
targets progressively increased (Fig. 1). Patients reaching
hormonal endpoints did not have different basal hormonal
levels vs. those who did not (28.5 24.6 vs. 30.6 32.3
g/liter for GH, 863 315 vs. 919 358 g/liter for IGF-I;
P 0.78 and 0.51, respectively). Patients starting from higher
basal GH levels (vs. the median value of the series, i.e. 24
g/liter) reached hormonal endpoints in the same percentage of those starting from lower ones (67.6 vs. 69.7% for GH,
70.6 vs. 66.7% for IGF-I; P 0.86 and 0.73, respectively) and
within the same time course (P 0.99 and 0.72, respectively,
by log-rank) (Fig. 2).
Hormonal decline was directly correlated with basal
levels (r 0.37 and 0.33 and P 0.002 and 0.0064 for GH
and IGF-I, respectively) and length of follow-up (r 0.34
and 0.34 and P 0.0048 and 0.0058, for GH and IGF-I,
respectively).
No difference in the achievement of hormonal endpoints
was observed between patients bearing macro- and microadenoma (62.5 vs. 84.2% for safe GH, 64.6 vs. 78.9% for normal IGF-I; P 0.0842 and 0.2533, respectively).
At multivariate analysis, the best predictors of final
hormonal values were the respective values obtained at 6
months. By receiver operating characteristic analysis, the
best predictor for the final attainment of safe GH values
was the achievement of GH levels less than 5 g/liter (area
under the curve, 0.9118 0.05; P 0.0001; sensitivity, 87%;
specificity, 94%; accuracy, 84%). IGF-I normalization was
predicted by the achievement of IGF-I levels less than 500
g/liter (area under the curve, 0.8057 0.0834; P 0.0001;
sensitivity, 86%; specificity, 75%; accuracy, 81%).

FIG. 1. Percentage of patients achieving or not achieving (white and

black bars, respectively) safe GH (top) and normal age-matched IGF-I
(bottom) levels during treatment. Shown on the horizontal axis (for
both panels) are months (upper line) elapsed after treatment start and
number of patients (lower line) evaluated at each period.

Tumor size

Semiquantitative evaluation. None of the patients experienced

progression of tumor growth.
Tumor shrank in 55 patients (82.1%). Shrinkage was evident at the first evaluation in 80% of them, but in a few other
cases the tumor shrank after 24 months. Shrinkage was progressive in 46% of patients (in 93% of patients with the more
prolonged follow-up). In three patients (two bearing microand one macroadenoma), the adenoma disappeared. In five
patients, a progressive (up to 30 96 months) reduction from
macroadenoma with extrasellar extension to empty sella occurred. In three other patients, in whom basal MRI suggested
the initial invasion of the cavernous sinus, follow-up imaging
showed the clear visualization of the lateral border of the
tumor, outside of the sinus itself.
Basal hormonal values in patients whose tumor shrank
were higher than in patients whose tumor did not (35 33
vs. 15 7 g/liter for GH, 1000 356 vs. 765 187 g/liter
for IGF-I; P 0.0095 and 0.0351, respectively), and IGF-I

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J Clin Endocrinol Metab, April 2006, 91(4):13971403

Cozzi et al. Primary Medical Therapy of Tumor in Acromegaly

FIG. 2. Influence of basal GH levels (below or above 24 g/liter, median of the

series, depicted by circles and black lines,
and triangles and gray lines, respectively) on hormonal endpoints evaluated
by log-rank test: A, the achievement of
safe GH levels; B, IGF-I normalization.

normalization occurred more frequently (75 vs. 20%; P

0.0067).
Tumor shrank more often in the younger than in the elderly patients (87 vs. 56%; P 0.0202, using as cutoff the
median age of the series, i.e. 56 yr).
The achievement of both hormonal and volumetric endpoints was obtained in 44.8% of patients. In most patients,
tumor shrinkage occurred before hormonal normalization.
In 35%, tumor shrank but GH did not reach a safe value. In
3%, no shrinkage occurred notwithstanding GH normalization. Neither safe GH nor tumor shrinkage was obtained in
15% of patients. Tumor shrank in 94 and 71% of patients
achieving or not, respectively, safe GH values.
Quantitative evaluation

Tumor volume decreased from 2101 2912 to 1010 2196

mm3 (P 0.0001). Percent decrease vs. baseline was 62 31%

(median, 67%; range, 0 99%). Tumor size decreased less than

25% of basal volume in 18% of patients, by 26 50% in 12%,
and by more than 50% in 70%. In particular, tumor shrank
more than 75% in 44%. Volumetric decrease was progressive:
28 19, 53 26, 69 14, and 91 7% at 6, 12, 24, and 36
months, respectively (P 0.0001).
Basal GH/IGF-I levels and tumor size were not correlated,
but basal GH values were significantly correlated with volumetric changes (r 0.38; P 0.0247); i.e. the greater the basal
GH values, the greater the shrinkage. During treatment,
there was a correlation between volumetric and hormonal
changes (r 0.54 and 0.43; P 0.0009 and 0.0107 for GH and
IGF-I, respectively); i.e. the greater GH/IGF-I suppression,
the greater the shrinkage. Final tumor volume was inversely
correlated to follow-up length (r 0.32; P 0.0354); i.e. the
longer the follow-up, the lower the final tumor volume.
Volumetric decrease in patients achieving hormonal tar-

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Cozzi et al. Primary Medical Therapy of Tumor in Acromegaly

gets was slightly higher than that obtained in patients who

did not (71 23 vs. 46 38%; P 0.0554).
Patients with macroadenoma showed tumor shrinkage
more frequently than patients bearing microadenoma (81 vs.
53%; P 0.0196). The absolute quantitative reduction was far
greater in the former group (1353 1555 vs. 240 182 mm3;
P 0.05), and percent decrease in tumor volume vs. baseline
was similar (64 30 vs. 56 34%; P 0.6053).
Figure 3 shows quantitative reduction in tumor size according to basal MRI characteristic of the adenoma.
Pituitary function

Prolactin, free T4, and urinary free cortisol levels did not
change throughout treatment (data not shown).
Normal gonadal function was resumed in the only amenorrheic female in fertile age, and in seven of 11 hypogonadal males, in whom treatment increased testosterone from
2.9 1.3 to 3.9 1.6 g/liter (P 0.0166), restoring eugonadism within 6 months. This result was not related to tumor
size or to its change during treatment or to GH/IGF-I
changes.
Metabolic effects (Table 2)

Mean fasting glucose, HbA1c, and cholesterol levels did

not change. Triglycerides decreased significantly (P 0.01).
Individual HbA1c became pathological in 33% of patients.
In diabetic patients, HbA1c decreased in 45% and increased
in 45%.
Adverse effects

Gallstones or biliary sludge appeared in 12% of patients.

One patient, who had transiently stopped OCLAR treatment,
required urgent surgical treatment for acute cholecystitis.
Discussion

Neurosurgery is regarded as the first therapeutic option in

acromegaly (10, 17). Its success rate is, however, highly de-

FIG. 3. Tumor size (mean SD, in mm3) before and during treatment
(white and hatched bars, respectively) evaluated (from left to right) in
the whole series, in patients bearing microadenoma, macroadenoma,
and invasive adenoma (both micro- and macroadenoma, as defined in
Table 1). *, P 0.05.

J Clin Endocrinol Metab, April 2006, 91(4):13971403

1401

pendent on preoperative GH values, tumor size, and neurosurgeons skills (11, 12, 18). Moreover, long-term relapse
(after 10 yr) has been reported in 19% of patients supposedly
cured at the postoperative evaluation (19). The role of radiotherapy has been debated in recent years, because of its
low efficacy (20, 21), occurrence of new hypopituitarism,
increased cerebrovascular mortality, and occurrence of second neoplasm (7, 22). -Knife radiosurgery does not seem to
obtain better results (23). The role of pharmacotherapy has
instead increased, mainly after the development of SA, octreotide (24), and its long-acting formulation OCLAR
(2528).
Following a pioneering study (14), which showed that
primary medical treatment of acromegaly with sc octreotide
was as effective as in patients previously unsuccessfully operated on, a few other reports strengthened the possibility of
treating selected patients with SA only. In this prospective
long-lasting open study in 67 consecutive naive nonselected
acromegalic patients mainly affected by macroadenoma,
OCLAR normalized GH and IGF-I values in 68.7 and 70.1%,
respectively. These figures are similar to those reported both
in a few small series of PT patients (29, 30), and in mixed
series (adjuvant and PT) (26, 31). In contrast with a metaanalysis (28) showing that the likelihood of achieving hormonal endpoints is greater in patients starting from lower
basal GH levels, we show that our patients with initial higher
basal GH values achieve hormonal targets as patients with
basal lower levels and with the same time course. In agreement with our previous report (27), we thus confirm that the
achievement of hormonal endpoints is quite independent
from basal hormonal values. The reason for the discrepancy
with data reported in the meta-analysis (28) is unclear.
Another interesting finding in agreement with our previous work (27) is the ability to predict the final outcome of PT
with OCLAR on the basis of early results (with 86% sensitivity and 75% specificity for IGF-I value 500 g/liter at 6
months in predicting IGF-I normalization).
We observed tumor size shrinkage in 82.1% of patients,
more frequently in macro- than in microadenoma, as already
reported (27, 29, 32), and quantitatively greater in macroadenoma, as in the initial reports on this topic (30, 31). Quantitative tumor size reduction in this series was impressive,
being greater than 50% in 70.6% and greater than 75% in
44.1% of cases. Moreover, shrinkage was progressive in
many patients, the adenoma disappeared in three (as once
reported) (33), and empty sella occurred in other five. This
finding, which is in contrast with a recent review (34), confirms that the fraction of patients whose tumor shrinks while
on treatment with OCLAR is far higher among primarily
treated cases, as already reported (32). The progressive
shrinkage of the adenoma, up to empty sella in a few cases,
contrasts with the previous knowledge about the effects of
SA on tumor volume in acromegaly. Although the early
reported results on this topic were variable (35), present data
strongly point out that the antitumor effect exerted by SA in
primarily treated acromegalic patients resembles what happens in macroprolactinoma patients treated by dopamine
agonist drugs (36).
Tumor shrank also in patients who did not reach safe GH
levels, as already reported (reviewed in Ref. 32); this dis-

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J Clin Endocrinol Metab, April 2006, 91(4):13971403

TABLE 2. Metabolic data (mean

Cozzi et al. Primary Medical Therapy of Tumor in Acromegaly

SD)

Fasting glucose (g/liter)

Glucose at 120 min after OGTT (g/liter)
HbA1c (%)
Total cholesterol (g/liter)
High-density lipoprotein cholesterol (g/liter)
Low-density lipoprotein cholesterol (g/liter)
Triglycerides (g/liter)

crepancy might be explained by the different molecular

mechanisms involved in inhibition of GH secretion and induction of tumor shrinkage (37). Hormonal normalization
was correlated to volumetric changes; i.e. the greater the
shrinkage, the greater the hormonal decrease, and the higher
the basal GH values, the greater the shrinkage. Moreover,
IGF-I normalization was much more frequent in patients
whose tumor shrank. So the main features (GH levels and
adenoma size) universally known to be limiting factors to the
success rate of neurosurgery (12) seem to play a favoring role
for OCLAR therapy in this series.
OCLAR shrank the tumor also in patients with clearly
invasive adenoma, but invasiveness did not revert. In contrast, in some cases with doubtful invasion of the medial wall
of the cavernous sinus at the first MRI, shrinkage clearly
allowed us to better distinguish the lateral limit of the adenoma. So the pretreatment neuroradiological finding of invasiveness might sometimes be misleading, and the control
MRI, showing a better definition of tumor limits, could
change the final therapeutic strategy.
In our series, OCLAR was interrupted in the three patients
whose adenoma disappeared during treatment only. In one
of them with a microadenoma, GH/IGF-I levels remained
normal even 18 months after drug withdrawal, and MRI
control did not show any change. In the other two patients,
GH/IGF-I levels increased again slowly and treatment was
restarted soon, before MRI control could show any regrowth
of the adenoma.
The safety treatment profile was excellent. Thyroid and
adrenal function were not impaired; gonadal function improved significantly, allowing restoration of eugonadism in
most hypogonadal patients. This finding is analogous to the
recovery of hypogonadism during dopaminergic treatment
of macroprolactinoma (36).
Glucose metabolism was not impaired in the whole group;
glucose balance improved in 45% and worsened in 45% of
diabetic patients as well as in 33% of nondiabetics. The worsening of glucose metabolism during OCLAR treatment has
been considered a serious side effect of SA treatment, in
contrast to the improvement observed during GH-antagonist
treatment (38). Whereas most studies did not report any
significant change (reviewed in Ref. 39), others found increased fasting glucose levels in previously euglycemic patients, whereas glucose response in diabetic patients was
unpredictable (40). Cholesterol was unaffected by treatment,
whereas triglycerides decreased. The improvement of lipid
profile during treatment with octreotide was already reported (41).
Biliary function was unaffected in most patients of this
series, but a single patient required urgent surgery for acute

Basal

On treatment

1.13 0.36
1.54 0.55
6.2 1.3
2.12 0.49
0.48 0.07
1.36 0.52
1.42 0.54

1.13 0.26
1.71 0.57
6.3 1
2.15 0.49
0.56 0.11
1.37 0.57
1.11 0.37

0.45
0.2489
0.2378
0.75
0.23
0.78
0.01

cholecystitis. The low rate of biliary dysfunction in this series

may depend on the diet assumed in our country as well as
on the mechanism of action of the depot formulation of
octreotide. The patient who required acute surgery had
stopped the drug for a short period of time. In this situation,
gallbladder contractility might be restored, thus causing
acute impaction of stones on biliary tracts (42).
In conclusion, PT with OCLAR normalizes GH/IGF-I levels and reduces tumor volume in a very high percentage of
patients; shrinkage is most impressive in the patients with
the highest GH levels and the largest tumors. These data,
coupled to the improvement of gonadic function and safety
profile, point out that in selected acromegalic patients (huge
and/or invasive adenoma with high GH levels, poor candidates to surgical cure), OCLAR should be the first treatment
of the disease, as in the patients at high surgical risk due to
disease-related comorbidities. The high prevalence and the
impressive degree of tumor shrinkage obtained with OCLAR
treatment might encourage us to evaluate primary OCLAR
adoption for improving surgical prognosis and even in patients with initial visual field defects. Moreover, the shrinkage of tumor, initially regarded as invasive, could change the
final therapeutic strategy in some patients.
In a contemporary patient-oriented approach to acromegalic disease, surgical and medical therapy should not be
mutually exclusive, but rather they should be complementary. When primary SA treatment in patients that are not
amenable to surgical cure does not achieve hormonal targets,
surgical debulking may improve subsequent response to a
new challenge with SA, according to recent data obtained in
a selected series of patients partially sensitive to SA (43, 44).
Acknowledgments
Received October 26, 2005. Accepted January 25, 2006.
Address all correspondence and requests for reprints to: Dr. R. Cozzi,
Viale Ezio 5, I-20149 Milano, Italy. E-mail: renatocozzi@tiscali.it.
The authors have no potential conflicts of interest to declare.

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