A randomized placebo-controlled study in patients with a Gallium-68 DOTATATE PET/CT positive, clinically non-functioning pituitary macroadenoma (NFMA) of the effect of Lanreotide autosolution on Tumor (adenoma) size

In patients with clinically non-functioning pituitary macroadenomas (NFMA), the
current therapeutic approach is to substitute any hormonal deficits, and to
perform transsphenoidal surgery if necessary, based on optic chiasm compression
or visual field defects. In Amsterdam, approximately 40 of these patients per
year undergo surgery. In the literature, remission rate after surgery is
estimated to be about 44%, which is substantially lower than in other pituitary
tumor types, and recurrence rate is about 11% during an average follow-up
period of 5 years. The available evidence concerning treatment and follow-up of
NFMA is based exclusively on small, observational studies, and there is a
remarkable lack of randomized studies. Whereas medical therapy is regarded as
first-line treatment in prolactinoma patients, the role for medical therapy in
patients with NFMA is controversial. It has been known for some decades that
NFMA may express somatostatin receptors, as seen in surgical specimens and in
vivo, using Indium-111 pentetreotide SPECT (*Octreoscan*). Based on these
observations, a limited number of small studies has been conducted focusing on
octreotide treatment and showing conflicting results on tumor size reduction.
It is important to note that the normal anterior pituitary gland takes up
Indium-111 pentetreotide as well. However, the spatial resolution of SPECT is
insufficient to differentiate NFMA from normal anterior pituitary tissue. The
more recent development of Gallium-68 DOTATATE PET/CT imaging in pituitary
tumours shows a superior sensitivity and spatial resolution, which allows for
accurate quantification of radioligand uptake within neuroendocrine tumours.
Thus, somatostatin analogues may have potential in some NFMA patients, but
there is a remarkable lack of randomized and controlled studies. Furthermore,
it is not possible at present to predict which patients will respond to
somatostatin analogues.

To investigate the efficacy of lanreotide therapy as compared to placebo in
patients with NFMA and positive pituitary somatostatin receptor imaging using
Gallium-68 DOTATATE PET/CT, on tumor size.

Randomized, double-blind, placebo-controlled trial

A Gallium-68 DOTATATE PET/CT will be performed in suitable patients after
obtaining informed consent. The first 44 patients with a positive PET/CT will
be randomized into two treatment groups:
Group 1 will receive monthly subcutaneous injections of lanreotide (18 months)
Group 2 will receive monthly subcutaneous injections of placebo (18 months)

Interested patients with NFMA will be invited for visit 1 at their own center
(informed consent, in- and exclusion criteria, quality of life questionnaire,
physical exam, venipuncture, pituitary MRI, and * if applicable * a pregnancy
test). The physical exam, venipuncture and pituitary MRI are part of standard
NFMA evaluation. Included patients will undergo a Gallium-68 DOTATATE PET/CT
scan. For AMC based patients this scan can take place on the same day during
visit 1 at the AMC; for VUmc and LUMC patients the scan will be planned on a
second visit. The scan is very well tolerated and the total radiation exposure
is estimated at 3.1 mSv (millisievert). The first 44 patients with a positive
PET/CT will be randomized to receiving a deep subcutaneously injection of
lanreotide autosolution 120 mg, or to receiving placebo injection consisting of
saline once every 4 weeks for 18 months (18 visits). The injections will either
be administered at the clinical Endocine Unit of the AMC by an endocrine nurse,
or at home by trained nurses from Eurocept Homecare.
Treatment with lanreotide autosolution 120 mg was shown to be safe and
well-tolerated as a first-line therapy in patients with growth hormone
secreting pituitary adenomas. It does carry a small risk of developing
symptomatic gall stones. In ~10% of patients it may cause diarrhea, loose
stools, or abdominal pain, especially after the first injection. In <10% it may
cause injection site reactions.
Every 24 weeks or so a study visit takes place, consisting of a short physical
examination (± 5 minutes), blood tests (8 vials via one venipuncture, total
volume 36 milliliters), a quality of life questionnaire and documentation of
adverse events. Pituitary MRI will be repeated after 6 months and after 18
months. Again, the physical exam, the blood tests and the MRI are part of
standard NFMA care.
The total number of study visits to the hospital depends on where the
injections are administered. The minimum is 4 visits for AMC patients and 5
visits for VUmc and LUMC patients, the maximum is 21 visits. During the study
period, patients are not deprived of any standard therapy. The benefit is
potentially reduced NFMA growth rate, which may postpone or obviate
transsphenoidal surgery or radiotherapy. If this study shows a positive effect
on tumor size, standard treatment of NFMA could be improved in a major way.