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Macroprolactinoma Shrinkage during Cabergoline Treatment Is Greater in Naive Patients Than in Patients Pretreated with Other Dopamine Agonists: A Prospective Study in 110 Patients¹

Departments of Molecular and Clinical Endocrinology and Oncology (A.C., A.D.S., M.L.L., R.P., G.L.), Neurosurgery (P.C.), Radiology (F.D.S., S.C.), and Pharmacology (L.A.), Federico II University of Naples, and Section of Endocrinology, Cardarelli Hospital (F.S., R.V.), 80131 Naples, Italy

Address all correspondence and requests for reprints to: Annamaria Colao, M.D., Ph.D., Department of Molecular and Clinical Endocrinology and Oncology, Federico II University, Via S. Pansini 5, 80131 Naples, Italy. E-mail: colao{at}unina.it

To investigate whether previous treatment with bromocriptine (BRC) or quinagolide (CV) impairs a subsequent response to long-term cabergoline (CAB) treatment, we prospectively studied 110 patients with macroprolactinoma. Four groups of patients were considered: 1) naive: 26 untreated patients with a mean serum PRL levels of 1013.4 ± 277.7 µg/L (±SEM; range, 185.5–5611 µg/L); 2) intolerant: 19 patients previously shown to be intolerant of BRC treatment with a mean serum PRL level of 539.4 ± 172.2 µg/L (range, 174-3564 µg/L); 3) resistant: 37 patients shown to be resistant/hyporesponsive to BRC, CV, or both, with a mean serum PRL level of 602.6 ± 136.8 µg/L (range, 148-3511 µg/L); and 4) responsive: 28 patients previously treated with BRC or CV for 1–5 yr, achieving normoprolactinemia and restoration of gonadal function, but no longer treated with BRC or CV because of poor compliance or because the drug was not available. After a 15- to 30-day washout period, the serum PRL level was 397 ± 43.1 µg/L (140–978 µg/L). CAB treatment was given at doses ranging 0.25–3.5 mg weekly for 1 yr to 110 patients, for 2 yr to 104 patients, and for 3 yr to 81 patients. Magnetic resonance imaging was performed before and after 12, 24, and 36 months of CAB treatment to evaluate significant tumor shrinkage (>80% reduction of pretreatment tumor volume).

Among the 26 naive patients, normoprolactinemia was achieved in 21 (80.8%) after 1–6 months at 0.25–2 mg/week and in 5 patients after 24 months at 0.5–3 mg/week. Tumor volume was reduced from 1431.5 ± 310.3 to 47.2 ± 21.5 mm³ (P < 0.0001); average tumor shrinkage was 92.1 ± 2.9%; significant tumor shrinkage was observed in 92.3% of patients, and tumor mass completely disappeared in 16 patients (61.5%).

Among the 19 intolerant patients, normoprolactinemia was achieved in 18 (94.7%) after 1–6 months of CAB treatment at 0.25–1 mg/week. One patient remained mildly hyperprolactinemic. Tumor volume was reduced from 1925 ± 423.1 to 842.0 ± 330.7 mm³ (P < 0.001); average tumor shrinkage was 66.2 ± 6.4%; significant tumor shrinkage was obtained in 42.1% of patients, and tumor mass completely disappeared in 4 patients (21%).

Among the 37 resistant patients, normoprolactinemia was achieved in 19 (51.3%) after 6–12 months at 1–2 mg/week and in the remaining 18 patients after 18–24 months at 3–3.5 mg/week. Tumor volume was reduced from 1208.0 ± 173.7 to 471.2 ± 87.3 mm³ (P < 0.005); average tumor shrinkage was 58.4 ± 4.9%; significant tumor shrinkage was obtained in 10 of 33 patients (30.3%), and in no patient did tumor mass completely disappear.

Among the 28 responsive patients, normoprolactinemia was achieved in 23 (82.1%) after 1–6 months at 1–2 mg/week and in 5 patients after 12 months at 3 mg/week. Tumor volume was reduced from 1351.3 ± 181.5 to 757.1 ± 193.6 mm³ (P < 0.01); average tumor shrinkage was 59.2 ± 6.2%; significant tumor shrinkage was obtained in 10 of 26 patients (38.4%), and tumor mass completely disappeared in 4 patients (15.4%).

Nadir PRL levels and percent tumor shrinkage during CAB treatment in naive patients were significantly lower (P < 0.001) and higher (P < 0.001), respectively, than those in the remaining three groups, and the average weekly dose of CAB in resistant patients was significantly higher (P < 0.001) than that in the remaining three groups. A significant association was found between tumor shrinkage and previous treatments (² = 27.1; P < 0.0001). At the multistep correlation analysis, nadir PRL levels were the strongest predictors of tumor shrinkage (r² = 0.556; P < 0.0001), followed by CAB dose (r² = 0.577; P < 0.0001). The tolerability was excellent in 105 patients (95.4%).

In conclusion, the prevalence of macroprolactinoma shrinkage after CAB treatment at standard doses for 1–3 yr was higher in naive patients (92.3%) than in intolerant (42.1%), resistant (30.3%), and responsive patients (38.4%). Thus, CAB can be employed as first line therapy in macroprolactinomas. The more PRL levels were suppressed, the more tumor shrinkage was obtained.

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