Dopamine agonist resistant prolactinomas: any alternative medical treatment?

Abstract

Consensus guidelines recommend dopamine agonists (DAs) as the mainstay treatment for prolactinomas. In most patients, DAs achieve tumor shrinkage and normoprolactinemia at well tolerated doses. However, primary or, less often, secondary resistance to DAs may be also encountered representing challenging clinical scenarios. This is particularly true for aggressive prolactinomas in which surgery and radiotherapy may not achieve tumor control. In these cases, alternative medical treatments have been considered but data on their efficacy should be interpreted within the constraints of publication bias and of lack of relevant clinical trials. The limited reports on somatostatin analogues have shown conflicting results, but cases with optimal outcomes have been documented. Data on estrogen modulators and metformin are scarce and their usefulness remains to be evaluated. In many aggressive lactotroph tumors, temozolomide has demonstrated optimal outcomes, whereas for other cytotoxic agents, tyrosine kinase inhibitors and for inhibitors of mammalian target of rapamycin (mTOR), higher quality evidence is needed. Finally, promising preliminary results from in vitro and animal reports need to be further assessed and, if appropriate, translated in human studies.

Hyperprolactinaemia

“…Normalization of PRL and/or tumour shrinkage cannot be achieved with DA treatment in all cases of prolactinomas [25,109]. Prolactinomas are labelled as DA resistant due to either failure to achieve normoprolactinaemia and/or failure to achieve 50% reduction in tumour size with maximum tolerated DA dose (can be up to 30 mg daily for bromocriptine or 12 mg weekly for cabergoline [110,111]) after at least 6 months of treatment [109]. DA resistance occurs in approximately 20 to 30% of patients on bromocriptine and around 10% of patients on cabergoline [109].…”

“…Prolactinomas are labelled as DA resistant due to either failure to achieve normoprolactinaemia and/or failure to achieve 50% reduction in tumour size with maximum tolerated DA dose (can be up to 30 mg daily for bromocriptine or 12 mg weekly for cabergoline [110,111]) after at least 6 months of treatment [109]. DA resistance occurs in approximately 20 to 30% of patients on bromocriptine and around 10% of patients on cabergoline [109]. Male sex, younger age at diagnosis, tumour invasiveness (particularly in the cavernous sinus) and size >4 cm have been proposed as clinical factors associated with DA resistance [109,112].…”

“…DA resistance occurs in approximately 20 to 30% of patients on bromocriptine and around 10% of patients on cabergoline [109]. Male sex, younger age at diagnosis, tumour invasiveness (particularly in the cavernous sinus) and size >4 cm have been proposed as clinical factors associated with DA resistance [109,112]. In such cases, switching bromocriptine to cabergoline is an option, leading to normalization of PRL in 80 to 85% of patients [109].…”

“…Male sex, younger age at diagnosis, tumour invasiveness (particularly in the cavernous sinus) and size >4 cm have been proposed as clinical factors associated with DA resistance [109,112]. In such cases, switching bromocriptine to cabergoline is an option, leading to normalization of PRL in 80 to 85% of patients [109]. On the other hand, changing cabergoline to bromocriptine is rarely effective [111] but systematic data are not available.…”

“…For patients already on cabergoline, dose escalation is another option, as a number of them (around 15 to 20%) may require higher than the conventional doses of 2 mg per week [25,111]. It is uncommon for a prolactinoma initially responsive to DA to become resistant to this treatment; if this occurs, adherence to the DA should be confirmed [43,109,111]. Transsphenoidal surgery and radiotherapy are second and third line management options, respectively, for resistant prolactinomas, as discussed below [25].…”