The Cabergoline-Resistant Prolactinoma Patient: New Challenges

The Cabergoline-Resistant Prolactinoma Patient: New Challenges
-Molitch M. The Journal of Clinical Endocrinology & Metabolism December 1, 2008 vol. 93 no. 12 4643-4645, doi: 10.1210/jc.2008-2244

• "11 of 60 previously untreated patients (18.3%) required more than 2 mg/wk cabergoline to normalize PRL levels. Of these, four required 3 mg/wk, two required 6 mg/wk, four required 9 mg/wk, and one required 11 mg/wk to normalize PRL levels."
  
• "Of 150 patients, normalization of PRL was eventually achieved in all but one, but doses had to be raised to high levels in many."

Guidelines of the Pituitary Society for the diagnosis and management of prolactinomas

Guidelines of the Pituitary Society for the diagnosis and management of prolactinomas
-Casanueva F, et al. Clinical Endocrinology (2006) 65, 265–273

• "Doses [of cabergoline] over 3 mg per week are rarely necessary."

Cabergoline Resistance in Pediatric Prolactinomas

Cabergoline Resistance in Pediatric Prolactinomas
-Spinks J, et al. Journal of Pediatric Hematology/Oncology May 2009 - Volume 31 - Issue 5 - pp 377-379 doi: 10.1097/MPH.0b013e31819b71eb

• "We report 3 cases of cabergoline resistance in adolescents with prolactinomas. All patients failed to respond to conventional doses of cabergoline."

Dopamine agonist-resistant prolactinomas

Dopamine agonist-resistant prolactinomas
-Oh MC, Aghi MK Journal of Neurosurgery 2011 May;114(5):1369-79. published online January 7, 2011; DOI: 10.3171/2010.11.JNS101369.

• "Dopamine agonist-resistant prolactinomas exhibit aggressive behavior and tend to be large, invasive, hyperangiogenic tumors with high mitotic indices, which makes their management via surgery, radiosurgery, or alternative medical therapies challenging, thus underscoring the need for novel medical therapies or treatment regimens that target these lesions."
  
• "...slightly less than 10% of patients with prolactinomas do not experience normalization of their prolactin levels in response to dopamine agonists, and harbor tumors that are resistant to dopamine agonist therapy."
  
• "...a minimum pharmacological definition of dopamine agonist resistance would seem to require a failure to respond to 3 months of treatment with up to 3.5 mg of cabergoline per week."
  
• "Although very rare, secondary or acquired resistance to dopamine agonist therapy has also been described, in which patients who were initially responsive to... either bromocriptine or cabergoline, later develop dopamine agonist resistance, with elevated prolactin levels and sometimes an enlarging tumor volume several years after beginning treatment... According to a recent report... there have been only 5 reported instances of patients who demonstrated secondary resistance to dopamine agonist therapy (2 to bromocriptine and 3 to cabergoline).
  
• DARPs (dopamine agonist resistant prolactinomas) are more likely to exhibit cavernous sinus invasion... [71% vs 10% for dopamine agonist-responsive prolactinomas]."
  
• "DARPs typically do not metastatize."
  
• "Transsphenoidal surgery is recommended for prolactinomas instead of medical treatment if
  • ...2) inadequate prolactin reduction despite high cabergoline doses...
    
  • 3) a female patient desires fertility, which may not occur while on dopamine agonists...
    
  • 5) the patient cannot tolerate dopamine agonist therapy due to side effects.
• transsphenoidal surgery:
  • prolactin was normalized in 36% of patients with DARPs in one study.
    
  • prolactin was normalized in 75% of patients with DARPs that were microprolactinomas.
    
  • "Temozolomide... has been used to treat 3 patients with cabergoline-resistant DARPs... with good results in all 3 cases."

Prolactinomas: Diagnosis and Treatment: Management

Prolactinomas: Diagnosis and Treatment: Management
-Nassiri F, et al. Medscape Education CME Released: 02/29/2012.

• "Despite the effectiveness of [dopamine agonists]... some [patients] do not respond at therapeutic levels or higher. Such patients are considered to be DA resistant. The mechanism of resistance seems to be mediated by a decreased number of D2 receptors without a decreased affinity for DA agonists, and an altered signal transduction mechanism."
• "In resistant patients, treatment options include switching DA agonists, increasing DA agonist dosage beyond convention and surgery and/or radiotherapy."
• "Although doses of 2 mg/week exceed recommended package levels for cabergoline, some patients may require up to 3 mg/day for normalization of PRL levels."
• "Temozolomide therapy has even reduced tumor volume and normalized PRL levels in a resistant macroprolactinoma suggesting a possible role for temozolomide in resistant prolactinomas."

MEN1 and pituitary adenomas

MEN1 and pituitary adenomas
-Delemer B. Service d’endocrinologie-diabète-nutrition

"MEN1 [pituitary] tumors seem more aggressive, invasive and resistant to treatment requiring a very careful long-life follow-up. Occurrence of these tumors can be described in the pediatric population and it can be the first and only manifestation of MEN1 for some years asking the question of the systematic screening for MEN1 gene mutation in pediatric population with pituitary adenoma."