Clinical data
To identify predictive factors of dopamine agonist resistance, we conducted a retrospective study based on a database of patients treated in a Belgian tertiary reference center from 2014 to 2016 after approval of the ethical commission of our hospital. From the moment of the start of the study, we went back in time to when a sufficient number of patients, determined in a power analysis, could be included.
Consent has been obtained from each patient after full explanation of the purpose and nature of all procedures. The inclusion criteria of the patients for this study were: age of 18 years or older, a confirmed prolactinoma and an available MRI before the start of therapy. The diagnosis of prolactinoma was based on the assessment of our endocrinologists. Here, clinical presentation, exclusion of other causes of hyperprolactinemia, MRI imaging and laboratory findings were taken into account. We considered the diagnosis of prolactinoma only in the presence of a corresponding MRI image and prolactin levels that were clearly elevated corresponding with levels at least 2 times higher than the upper limit of normal for microadenomas (except in one case) and at least 5 times higher than the upper limit of normal for macroadenomas and established on two separate occasions.
Patients with familial tumour syndromes such as multiple endocrine neoplasia type 1 (MEN1) were excluded.
Clinical data with possible predictive relevance were extracted from the patient’s records: sex, age, age at diagnosis, presence of sexual dysfunction (amenorrhea or oligomenorrhea, infertility, decreased libido, erectile disorder) or galactorrhea, presence of mass effects and the duration of the symptoms before diagnosis. Mass effects disembosom: headache, dizziness, visual defects (abnormal visual field or eye movement disorder) and cranial neuropathy.
The biochemical data we determined, were the levels of PRL, insulin like growth factor -I (IGF-I), thyroid stimulating hormone (TSH) and adrenocorticotropic hormone (ACTH) and we quoted the presence of sex hormone deficiency defined as decreased gonadotropins or testosterone.
Furthermore we examined biochemical data as well as different MRI variables such as the volume of the tumour (h x l x w x (π/6)); the shape of the tumour (being a sphere or bifocal); the intensity factor which is calculated as the ratio between the intensity of the tumour and the intensity of the grey matter (displayed in pixel value, PV), always consequently at the level of the superior temporal gyrus. Contrast enhancement, which is the ratio of the density factor on T1 after contrast to the value on T1 without contrast, was likewise computed. We also investigated parameters for follow up regarding the evolution of the tumour volume and the prolactin level.
The dosage of cabergoline was monitored during treatment in order to evaluate the response.
The dopamine agonist dosing regimen was clinically adjusted and examined as follows. Effect of DA treatment was re-evaluated at least every 3 months. If the treatment goal was achieved in terms of prolactin level and tumour size, that same dose would have been continued. If treatment goal was not achieved, the dose would be augmented after evaluation by the endocrinologists at the consultation.
When surgery was involved, a histological examination of the surgical specimen was always performed. Information about the Ki 67 (proliferation marker) level and the presence of sclerosis was hereby obtained. Sclerosis (augmentation of fibrous tissue) is considered negative when there was no mention of fibrosis, connective tissue or sclerosis in the operation report; and when it is not defined by the anatomy pathologist in the histological examination report of the surgical specimen.
Patients assigned to the responsive group had both prolactin normalization and a tumour volume shrinkage of ≥50% in coronal surface under dopamine agonist treatment. Resistance was concluded if no hormonal or tumoural response could be achieved after the next 1–2 consultations with a weekly dose up to 3.0 mg cabergoline (see definition).
However, in that case, if tolerated and with the patient consent, the dosage would further be increased. The response was monitored throughout the follow-up (at least 12 months) and changed if there was a response after that further dose escalation.
Thereafter; a comparative study between the 2 groups, responsive versus resistant prolactinoma patients was performed.