Neoplasms

All Conditions

Nervous System Diseases

Gland and Hormone Related Diseases

Behaviors and Mental Disorders

Rare Diseases

Adenoma

Pituitary Diseases

Pituitary Neoplasms

Prolactinoma

Hypothalamic Diseases

Brain Diseases

Central Nervous System Diseases

Endocrine System Diseases

Endocrine Gland Neoplasms

Hypothalamic Neoplasms

Supratentorial Neoplasms

Brain Neoplasms

Central Nervous System Neoplasms

Nervous System Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Quality of Life

Cardiotonic Agents

All Drugs and Chemicals

Anti-Dyskinesia Agents

Dopamine

Cabergoline

Bromocriptine

Dopamine Agonists

Quinagolide

Sympathomimetics

Dopamine Agents

Neurotransmitter Agents

Protective Agents

Patients in the intervention groups will be referred to one of the participating neurosurgical centers, for surgical consultation. After this consultation, the patient may choose to continue with surgery or not.

Patients in the standard care groups will receive treatment as usual as described by the US Endocrine Society.

Neurosurgical consultation consists of at least one consult with a neurosurgeon and at least one consult with an endocrinologist with relevant experience. If the multidisciplinary team (MDT) agrees the patient is a good surgical candidate, the patient is asked consent for surgery, as is a custom part of preoperative requirements. When the patient decides not to have the surgery, (s)he will receive standard medical treatment, but will continue study follow up in the intervention group.

Surgery only takes place if both the MDT and the patient agree to it and should then be planned within three months after randomization. Surgery is performed by one or two trained neurosurgeons in the hospital where the counseling took place. A standard, semi-protocolled, endoscopic trans-sphenoidal surgical resection of the prolactinoma is performed according to standard practice.

Endoscopic trans-sphenoidal adenoma resection

The treating physician adheres to the treatment protocol in general, but has freedom to choose treatment to his/her ideas how to deliver best care.

Current first line treatment consists of a dopamine agonists: cabergoline (currently the most used), bromocriptine or quinagolide. All dopamine agonists are taken orally, and the dosage may be raised based on its effect. It is usually titrated to achieve a normal or suppressed prolactin level and restoration of the gonadal axis. Dopamine agonist treatment is discontinued after 2 years of treatment, unless a normal prolactin level cannot be achieved. The dopamine agonist is restarted when prolactin levels rise after the medication is discontinued.

In standard care, surgical treatment is reserved for patients who don't tolerate medication, or whose adenoma fails to show a sufficient response. Patients in the control group with an intolerance for dopamine agonists or an insufficient response may be offered surgery as part of standard care.

Ingrid M Zandbergen, MD

Coordinating invesitgator

Local principal investigator

Coordinating investigator

Ingrid M Zandbergen

Nienke R Biermasz, MD, prof.

Wouter R van Furth, MD, PhD

This study aims to investigate if endoscopic trans-sphenoidal prolactinoma resection as a first line treatment, or as an equally valid second line treatment after a short (4-6 months) or long (\>2 years) period of pretreatment with a dopamine agonist is superior to standard care for several outcome parameters. The main objectives are to investigate this for quality of life and remission rate. The secondary objectives are to investigate this for biochemical disease control, recurrence rates, clinical symptom control, tumor shrinkage on MRI, pituitary functioning, the occurrence of adverse reactions to treatment, disease burden, and cost-effectiveness.

This partially randomized, preference trial design, comprises three unblinded randomized controlled trials (RCTs) and an observational study arm (PRolaCT-O) that compare neurosurgical counselling and potentially subsequent endoscopic transsphenoidal adenoma resection with current standard care (DA treatment). Patients with a non-invasive prolactinoma of limited size (\<2.5 cm) will be divided over the three RCTs based on duration of pre-treatment with DA: PRolaCT-1: newly diagnosed, treatment naive patients; PRolaCT-2: patients with limited duration of DA treatment (4-6 months); and PRolaCT-3: patients with persisting prolactinoma after DA treatment for \>2 years. PRolaCT-O will include patients who decline randomization or those with a clear treatment preference. After study inclusion and treatment allocation, all study procedures and follow up are equal for the three RCTs and PRolaCT-O and are therefore discussed as one.

PRolaCT - Three Prolactinoma RCTs

PRolaCT - Three Multicenter Prolactinoma Randomized Clinical Trials

Health-Related Quality of Life is defined as the score on the mental health scale of the Medical Outcomes Study (MOS) Short-Form Health Survey (SF-36), measured at T=12.

Disease remission is defined as normoprolactinaemia (a prolactin level below the upper limit of normal as defined by the laboratory site where it is measured), in the absence of dopamine agonist treatment for at least 3 months or an actual pregnancy that was established during at least 3 months absence of dopamine agonist treatment, measured at T=36.

Disease remission as defined under the primary outcome for remission, measured at T=27.

Disease remission as defined under the primary outcome for remission, measured at T=60

Biochemical disease control is defined as normoprolactinaemia (a prolactin level below the upper limit of normal as defined by the laboratory site where it is measured), or an actual pregnancy, with or without the use of a dopamine agonist, measured at T=12.

Disease recurrence is defined as recurrence of hyperprolactinaemia (a prolactin level \>2 times the upper limit of normal as defined by the laboratory site where it is measured) in the absence of dopamine agonist treatment, after a period of normoprolactinaemia (without dopamine agonist treatment). This is measured only in patients who have achieved disease remission at T=27, and is measured at T=36 and T=60.

Clinical symptom control is defined as the absence of physical and psychiatric symptoms of prolactinoma.

Tumor growth or shrinkage will be calculated as the percentage difference from baseline in tumor size (defined as the maximal diameter measured in mm) and tumor volume (calculated using Cavalieri's principle: tumor volume = 4/3 × pi (a/2 × b/2 × c/2) where a, b and c represent the diameters (in mm) in the 3 dimensions), measured at T=12 and T=36. It will be considered as a relevant shrinkage if tumor diameter or volume decreases at least 20%.

The functioning of the pituitary axes other than prolactin (i.e. gonadal, thyroidal, corticoid, growth hormone and ADH axes), measured when indicated upon judgement by the treating physician (e.g. when an axis was deviant at baseline of as part of routine follow up after surgery) at T=12 and T=36.

A pituitary axis will be considered normal when the associated measurement is within its normal range specific to the laboratory where it was measured in the absence of supplement treatment.

Treatment specific adverse effects:

- The occurrence of known complications to surgery (i.e. cerebrospinal fluid leakage, diabetes insipidus, syndrome of inappropriate ADH-secretion, nasal complaints, decreased sense of smell/taste, intradural hemorrhage, meningitis, visual loss or a new pituitary deficit), as documented in patients' medical records by the treating physician, measured at T=12.

Treatment specific adverse effects:

- Occurrence of known side effects to dopamine agonist treatment as documented with the National Cancer Institute Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE™) and a combined Impulse Control Disorder questionnaire at baseline, T=12, T=27 and T=36.

Described by the scores on all sub-scales of the SF-36, in addition to the primary outcome on health-related quality of life. Measured at baseline, T=12, T=27, T=36 and T=60.

Measured with the Hospital Anxiety and Depression Scale (HADS). This questionnaire uses 14 items; seven related to anxiety and seven to depression, to calculate anxiety and depression scores, ranging from 0 to 21.

Measured with the Leiden Bother and Needs Questionnaire at baseline, T=12, T=36 and T=60.

Measured every 6 months until T=36, with the iMTA Medical Consumption Questionnaire.

Measured every 6 months until T=36, with the iMTA Productivity Cost Questionnaire.

Measured at 3-6 month intervals, with the EQ-5D-5L.

Leiden University Medical Center

Coordinating Investigator

Antiparkinson Agents

Target dose for cabergoline is 2 mg/week.The medication is administered in the evening to minimize side effects. If intolerable side effects occur despite this, it may be necessary to treat with a lower dose than 2 mg per week.

Treatment scheme: 0.5 mg x 1 per week the first 2 weeks, then 0.5 mg x 2 per week the next 2 weeks, then 1 + 0.5 mg per week the next 2 weeks, then 1 mg x 2 per week (target dose) for the rest of the study

cabergoline

Stine L Fougner, md phd

Sven M Carlsen, md phd

Stine L Fougner, MD PhD

Sven M Carlsen, prof md

Due to lack of hormone overproduction in non-functioning pituitary adenomas (NFPAs), only the symptomatic adenomas or large adenomas with proven growth and risk for symptoms in near future will undergo pituitary surgery. The remaining adenomas are monitored regularly. Operation of these large adenomas will rarely remove all tumour tissue, and there is also a risk of worsening of pituitary function. Often, adenomas with the highest growth potential are operated several times and some also need radiation therapy, providing additional risk for pituitary failure. Unlike some of the hormone-producing adenomas, there is no established pharmacological treatment for NFPAs. However, there are a few non-randomized studies suggesting that treatment with dopamine agonists may slow growth, and also induce tumour shrinkage. At present, cabergoline is the dopamine agonist most widely used in the treatment of pituitary adenomas secreting prolactin.

Aim is to study the effect of medical treatment with cabergoline in non-functioning pituitary adenomas on the change in tumour volume.

Dopamine Agonist Treatment of Non-functioning Pituitary Adenomas

Dopamine Agonist Treatment of Non-functioning Pituitary Adenomas (NFPAs) - a Randomized Controlled Trial

This includes the percentage and absolute change in tumour volume, but also the number of patients with significant tumour shrinkage or tumour growth (defined by ≥ 10 % or ≥ 2 mm shrinkage/growth in at least one dimension)

measured by analysis of blood tests, basal and stimulation tests

as measured by analysis of echo cardiography

as measured by questionnaire visual files: clinical evaluation by ophthalmologist and perimetry

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
PRolaCT - Three Prolactinoma RCTs	NCT04107480	Prolactinoma Prolactin-Produ...	Endoscopic tran... Dopamine Agonis...	18 Years -	Leiden University Medical Center
PRolaCT - Three Prolactinoma RCTs	NCT04107480	Prolactinoma Prolactin-Produ...	Endoscopic tran... Dopamine Agonis...	18 Years -	Leiden University Medical Center
Dopamine Agonist Treatment of Non-functioning Pituitary Adenomas	NCT02288962	Pituitary Neopl... Adenoma	cabergoline	18 Years - 75 Years	St. Olavs Hospital

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