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Background Whether the withdrawal of treatment in patients with nontumoral hyperprolactinemia, microprolactinomas, or macroprolactinomas is safe and effective has been unclear. We performed an observational, prospective study of cabergoline (a dopamine-receptor agonist) withdrawal in such patients.
Methods The study population included 200 patients — 25 patients with nontumoral hyperprolactinemia, 105 with microprolactinomas, and 70 with macroprolactinomas. Withdrawal of cabergoline was considered if prolactin levels were normal, magnetic resonance imaging (MRI) showed no tumor (or tumor reduction of 50 percent or more, with the tumor at a distance of more than 5 mm from the optic chiasm, and no invasion of the cavernous sinuses or other critical areas), and if follow-up after withdrawal could be continued for at least 24 months.
Results Recurrence rates two to five years after the withdrawal of cabergoline were 24 percent in patients with nontumoral hyperprolactinemia, 31 percent in patients with microprolactinomas, and 36 percent in patients; with macroprolactinomas. Renewed tumor growth did not occur in any patient; in 10 female patients (22 percent) and 7 male patients (39 percent) with recurrent hyperprolactinemia, gonadal dysfunction redeveloped. In all diagnostic groups, prolactin levels at the time of recurrence were significantly lower than at diagnosis (P<0.001). The Kaplan–Meier estimated rate of recurrence at five years was higher among patients with macroprolactinomas and those with microprolactinomas who had small remnant tumors visible on MRI at the time of treatment withdrawal than among patients whose MRI scans showed no evidence of tumor at the time of withdrawal (patients with macroprolactinomas, 78 percent vs. 33 percent, P=0.001; patients with microprolactinomas, 42 percent vs. 26 percent, P=0.02).
Conclusions Cabergoline can be safely withdrawn in patients with normalized prolactin levels and no evidence of tumor. However, because the length of follow-up in our study was insufficient to rule out a delayed increase in the size of the tumor, we suggest that patients be closely monitored, particularly those with macroprolactinomas, in whom renewed growth of the tumor may compromise vision.
There is wide consensus that primary medical treatment of prolactinoma with dopamine agonists is preferable to surgery, not only because of the excellent clinical results of medical therapy but also because of the risk of recurrent hyperprolactinemia after unsuccessful surgery.12,13,14 A definitive cure of these tumors is considered possible, however, only with surgery or, in rare cases, with surgery plus radiation therapy.2 The results of withdrawal of medical therapy, based on scanty data obtained from small patient cohorts that were followed for short periods, have indicated that hyperprolactinemia recurs more often when treatment is withdrawn than when surgery is performed — for a rate of approximately 90 percent in patients with macroprolactinomas and 80 percent in patients with microprolactinomas.15,16,17,18,19,20,21 Renewed growth of the tumor appears to be uncommon but may occur after some delay and with a risk of compromised vision.15,16,17,18,19,20,21 To our knowledge, no systematic studies have investigated the effect of cabergoline withdrawal on rates of remission of prolactinoma, although preliminary reports have indicated that in 17 to 30 percent of patients, the levels of prolactin are in the normal range one year after the withdrawal of cabergoline.22,23 We report the results of a prospective study of cabergoline withdrawal in patients who were treated primarily with this compound.
Methods
Inclusion Criteria
Patients were eligible for our study if after treatment with cabergoline they had serum prolactin levels that were in the normal range and the tumor had disappeared or decreased in size by 50 percent or more from base line. Patients were considered for withdrawal of cabergoline only if the outer border of the tumor was 5 mm or more from the optic chiasm, without magnetic resonance imaging (MRI) evidence of invasion of one or both cavernous sinuses or any other critical area. Patients were required to continue follow-up after withdrawal for at least 24 months. To minimize the risk of errors in reading MRI scans, all patients continued to receive cabergoline therapy for 12 months after fulfilling the withdrawal criteria and before withdrawal of the medication. The study was approved by the ethics committee of Federico II University of Naples. All patients provided informed consent. In the period from 1994 to 1997, oral consent was obtained in the presence of a third party, and after 1997, written consent was obtained. All procedures were performed in accordance with the standard approach used to treat prolactinoma at Federico II University Hospital.
Patients
From January 1, 1994, through December 31, 1998, 354 patients (283 women and 71 men) in whom hyperprolactinemia was newly diagnosed received cabergoline as first-line therapy (194 patients with microprolactinomas, 135 patients with macroprolactinomas, and 25 patients with nontumoral hyperprolactinemia) (Figure 1). Subsequently, treatment was stopped in 57 patients (16 percent) because of pregnancy. Prolactin levels normalized in 273 of the remaining 297 patients (92 percent); 200 of these 273 patients (73 percent, 56 percent of the study cohort) fulfilled the criteria for cabergoline withdrawal and were included in the study (Table 1). Diagnostic criteria for macroprolactinoma were serum prolactin levels of 200 µg per liter or more and evidence on MRI of a pituitary tumor that was more than 10 mm in diameter. For microprolactinoma, the criteria were serum prolactin levels of 50 µg per liter or more and evidence on MRI of a pituitary tumor that was 10 mm or less in diameter. For nontumoral hyperprolactinemia, the criteria were serum prolactin levels above the normal range and evidence on MRI of a normal pituitary, without another explanation for an increased prolactin level, such as primary hypothyroidism or drug-induced hyperprolactinemia.24 No patient with nontumoral hyperprolactinemia or a microprolactinoma and only 31 of 103 (30 percent) of those with macroprolactinomas had panhypopituitarism. All male patients had a history of decreased libido and impaired sexual potency, and all female patients had a history of menstrual disturbances. Of 208 female patients, 111 (53 percent) had spontaneous or expressible galactorrhea. Of 103 patients with macroprolactinomas, 39 (38 percent) had visual-field defects, and visual loss occurred in 4 of these patients (10 percent).
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Cabergoline was administered orally at a single starting dose of 0.5 mg in the first week and then at a dose of 0.5 mg twice per week. After two months of treatment, the dose was adjusted every two months on the basis of suppression of serum prolactin. The dose of cabergoline was increased to 5 to 7 mg per week in patients in whom prolactin levels did not normalize11 and was reduced in patients in whom the prolactin levels declined to less than 5 µg per liter. Before the withdrawal of cabergoline, the dose was reduced to 0.5 mg per week in all patients; cabergoline was withdrawn only in patients whose prolactin levels remained normal after dose reduction.
Study Protocol
The few patients who had hypopituitarism received standard replacement therapy with recombinant human growth hormone (5 to 8 µg per kilogram of body weight per day subcutaneously), levothyroxine (50 to 100 µg orally per day), cortisone acetate (25 to 37.5 mg orally per day), and either estrogen–progestin (orally each day) or testosterone (250 mg by intramuscular injection monthly), as necessary.11 Serum insulin-like growth factor I, free thyroid hormone, and testosterone and serum and urinary sodium and potassium were measured periodically to assess the adequacy of the hormone-replacement therapy. At the time of enrollment, the serum prolactin level was calculated as the average of a 6-hour profile during which blood was sampled every 30 minutes from 8 a.m. to 2 p.m.; prolactin levels were measured at 8, 8:15, and 8:30 in the morning during treatment, and the average value was recorded. Prolactin levels were measured by radioimmunoassay (intraassay and interassay coefficients of variation, 5 percent and 7 percent, respectively; normal range, 5 to 25 µg per liter in women and 5 to 15 µg per liter in men). General clinical examinations were performed throughout follow-up. After the withdrawal of cabergoline, prolactin levels were measured every 15 days during the first month, then once a month for 5 months, quarterly during the second half of the first year, and every 6 months thereafter. This scheme was used for all the study subjects during follow-up, unless there was a recurrence. For patients in whom a recurrence developed, treatment was provided according to our current clinical protocol on the basis of prolactin levels.
Diagnosis of Recurrence
Recurrence was considered to have occurred if prolactin levels were above the normal range. To minimize the risk of renewed symptoms, cabergoline treatment was immediately restarted if clinical symptoms related to hyperprolactinemia reappeared or if repeated measurements of prolactin after 7 to 10 days confirmed hyperprolactinemia. Otherwise, follow-up was continued according to the study protocol.
MRI Studies
Tumor mass was evaluated with the use of MRI as previously reported.10 The MRI studies were performed with clinical 0.5-Tesla scanners from 1994 to 1999, 1-Tesla scanners from 2000 to 2001, and 1.5-Tesla scanners from 2002 on, with the use of T1-weighted gradient-recalled echo in the sagittal and coronal planes. For each measurement, 7 to 11 slices were obtained, at a thickness of 2 to 3 mm and an in-plane spatial resolution of 0.70 to 0.97 mm. Images were obtained before and after the administration of 0.1 mmol of gadolinium chelate (diethylene-triamine pentacetate). The maximal tumor diameter was calculated in millimeters. The MRI studies were performed before treatment with cabergoline; at 3, 6, and 12 months during the first year of treatment; and then every 6 to 12 months on the basis of the reduction in the size of the tumor. After the withdrawal of cabergoline, MRI was repeated every six months the first year and then yearly. If recurrent hyperprolactinemia was diagnosed, the patient underwent MRI at the time of diagnosis.
Ophthalmologic Examination
All patients with macroprolactinomas underwent testing for visual-field defects with the use of Goldmann–Friedmann perimetry, as well as visual acuity, at base line. The ophthalmologic examination was repeated every six months during cabergoline treatment in patients with visual disturbances. After the withdrawal of cabergoline, two patients were reexamined because of visual abnormalities due to atrophy of the optic nerve, despite the disappearance of tumor during treatment with cabergoline.
Statistical Analysis
Data are reported as means ±SD. Data analysis was performed with the use of SPSS software (SAS Institute). Mean values in the three study groups were compared with the use of paired and unpaired t-tests and analyses of variance. Categorical variables were compared with the use of Fisher's exact test. A Cox proportional-hazards regression analysis was used to determine which variables independently predicted recurrence of hyperprolactinemia, evaluated as the average prolactin value at the last follow-up visit after the withdrawal of cabergoline. We entered into the model only variables that had a P value of less than 0.01 in the univariate analysis. The Kaplan–Meier method was used to analyze the primary end point of recurrent hyperprolactinemia during long-term follow-up. Recurrence-free survival was measured from the date of cabergoline withdrawal to the date of relapse, and the data were censored at the date of the last follow-up visit. The log-rank test was used to compare recurrence-free survival curves. P values of less than 0.05 were considered to indicate statistical significance.
Results
Nontumoral Hyperprolactinemia
In the group of patients with nontumoral hyperprolactinemia, cabergoline was withdrawn after a median treatment period of 36 months at a median dose of 0.5 mg per week (Table 1). Of 25 female patients with nontumoral hyperprolactinemia, 6 (24 percent) had a recurrence after a median of 18 months (Table 2), but in none of them did symptoms reappear. In the remaining 19 of these patients (76 percent), hyperprolactinemia remained controlled at a median of 48 months after the withdrawal of cabergoline.
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In the group with microprolactinomas, cabergoline was withdrawn after a median treatment period of 48 months at a median dose of 1 mg per week (Table 1). In 63 of 105 patients, MRI studies of the pituitary gland showed no evidence of renewed tumor growth. In the remaining 42 patients, the tumor decreased by 55.5±4.8 percent (from 7.0±1.4 to 3.1±0.6 mm). In 32 patients (30 percent), hyperprolactinemia recurred after a median of 12 months; none of these 32 patients had MRI evidence of recurrent microprolactinomas. In 5 of 25 female patients (20 percent) oligomenorrhea developed; none of the 25 female patients had galactorrhea. Three of seven male patients (43 percent) noted decreases in sexual potency and libido, although their testosterone levels did not change. Hyperprolactinemia remained controlled in the remaining 73 patients (70 percent) at a median of 36 months after the withdrawal of cabergoline.
Macroprolactinoma
In the macroprolactinoma group, cabergoline was withdrawn after a median treatment period of 42 months at a median dose of 1 mg per week (Table 1). Of 70 patients with macroprolactinomas, MRI studies of the pituitary gland in 46 showed no evidence of renewed tumor growth. In the remaining 24 patients, tumor size decreased by 60.7±6.2 percent (from 16.9±4.1 to 6.6±1.6 mm). Twenty-five of the 70 patients (36 percent) had a recurrence of hyperprolactinemia after a median of 18 months; none of these 25 had MRI evidence of recurrent growth of the macroprolactinoma. Of 14 female patients, 5 noted renewed oligomenorrhea (36 percent), and 1 had recurrent galactorrhea (7 percent). Of 11 male patients, 4 (36 percent) reported decreased sexual potency and decreased libido, which were accompanied by a decrease in testosterone levels (from 4.2±0.5 to 3.2±0.4 µg per liter). In 45 patients (64 percent), hyperprolactinemia remained controlled at a median of 48 months after the withdrawal of cabergoline.
As shown in Table 2, in all three groups, the overall recurrence rate, the median time to recurrence, and the prolactin level at recurrence were similar. The average prolactin level was significantly lower at the last follow-up visit than at diagnosis in all groups (Table 2). The Kaplan–Meier estimate of the five-year recurrence rate was higher among patients with either macroprolactinomas or microprolactinomas who had remnant tumors on MRI before the withdrawal of cabergoline than among those who had no evidence of tumor on MRI (patients with macroprolactinomas, 78 percent vs. 33 percent, P=0.001; patients with microprolactinomas, 42 percent vs. 26 percent, P=0.02) (Figure 2). Sixty-three patients had recurrent hyperprolactinemia, more than half of them (56 percent) during the first year after the withdrawal of cabergoline, 33 percent during the second year, 11 percent during the third year, and none thereafter (P<0.001).
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Our study showed that, in general, remission of hyperprolactinemia persisted after the withdrawal of cabergoline, without any evidence of renewed tumor growth. Neither sex nor age was associated with the recurrence of hyperprolactinemia, and the maximal tumor diameter during treatment with cabergoline was the best predictor of the prolactin level at the last follow-up visit after withdrawal, with a hazard rate to predict recurrence of 19 percent.
The efficacy of the primary treatment of both microprolactinoma and macroprolactinoma with dopamine-agonist compounds and, more specifically, with cabergoline, is widely documented.7,8,9,10,11,22,23,24,25,26,27,28,29,30 Cabergoline therapy has also been successful in patients whose prolactinomas were resistant to bromocriptine or who could not tolerate bromocriptine,26,27 with a success rate of over 90 percent in patients with newly diagnosed prolactinomas.10,23,29 The most important shortcoming of medical treatment has been considered to be its theoretically lifelong requirement.
The results of bromocriptine withdrawal have been reported after a wide range of follow-up periods (8 to 240 months; median, 24). The results have been variable, with normoprolactinemia sustained in 7 to 38 percent of patients.15,16,17,18,19,20,21,31 Notably, an increase in tumor volume with clear reexpansion has been found in approximately 10 percent of cases.15,17 Renewed growth of the tumor after discontinuation of bromocriptine therapy, however, seems to depend on the duration of treatment before drug withdrawal: the tumors appear to be most susceptible to renewed growth after a course of treatment of less than 12 months.32,33,34,35
Withdrawal of cabergoline has been reported in only a few studies. One study reported persistent normoprolactinemia in 1 patient of 9 with a macroprolactinoma (11 percent) and 4 patients of 18 with microprolactinomas (22 percent) 12 months after withdrawal23; another reported that there was no change in prolactin levels in 24 percent of 25 patients after 3 to 60 months36 and in 31 percent of 32 patients who were treated for 3 to 24 months 12 months after withdrawal.22 In an earlier study, we found that normoprolactinemia persisted 12 months after withdrawal in 17 percent of 23 patients with microprolactinomas who were treated with cabergoline for 12 months.25 An important shortcoming of previous studies was the lack of criteria for timing withdrawal: in those studies cabergoline was apparently withdrawn after varying periods (12 months, on average), without systematic evaluation of the outcome of withdrawal with respect to prolactin suppression and tumor shrinkage.
Because the possibility of inducing long-lasting control of hyperprolactinemia without continuing pharmacologic treatment has profound consequences not only for patients' compliance but also for the costs of treatment, we designed our study to determine the rate of success of cabergoline withdrawal and potentially useful criteria for identifying patients with the highest likelihood of prolactin control after the discontinuation of cabergoline therapy. According to the literature on bromocriptine withdrawal,15,16,17,18,19,20,21,31 achieving normoprolactinemia is the first criterion and a mandatory one. We chose tumor shrinkage as an additional criterion and divided our patients on the basis of the extent of tumor shrinkage into two groups, those whose tumor disappeared and those in whom a 50 percent or greater reduction occurred from base line in a tumor mass that was not near the optic chiasm or invading the cavernous sinuses or other critical cerebral areas. Previous morphologic studies of tumor specimens obtained after long-term treatment with bromocriptine have shown atrophic tumor-cell nests, pyknosis, and cytolysis, as well as karyorrhexis, necrosis, fibrosis, hyalinosis, and inflammatory-cell infiltration, suggesting a cytocidal effect of the drug.37 We attribute our high rate of stable normoprolactinemia without tumor recurrence, even among patients with macroprolactinomas, to an effective antitumoral effect of cabergoline.
It should also be noted that even though patients whose MRI studies showed no evidence of tumor had a significantly lower rate of recurrence than those with visible tumors on MRI, 59 percent of patients with small, remnant microprolactinomas and 23 percent of those with small, remnant macroprolactinomas had persistent normoprolactinemia after cabergoline withdrawal. This finding suggests that in some of these patients the abnormalities detected on MRI may have been small, nonfunctioning lesions, fibrotic scars, or other nontumoral abnormalities (incidentalomas).
We excluded patients with certain conditions, such as pregnancy,38,39 previous surgery, and radiotherapy, that are known to facilitate the occurrence of normoprolactinemia after dopamine-agonist withdrawal. Menopause might be considered a factor that influences the reduction of hyperprolactinemia,40 but the rate of recurrence of hyperprolactinemia was similar among patients who were premenopausal and those who were postmenopausal. Remission of prolactinomas has also been described as part of the natural history of untreated tumors.41,42,43 However, even allowing for the possible role of this natural history in the outcome of microprolactinomas, it seems unlikely that macroprolactinomas would spontaneously regress. In our study, the overall rates of remission at five years as estimated by the Kaplan–Meier method were 76 percent among patients with nontumoral hyperprolactinemia, 67 percent among those with microprolactinomas, and 57 percent among those with macroprolactinomas, rates that are higher than those generally reported in the literature as spontaneous regression.
Our data support the concept of periodic withdrawal of cabergoline therapy, especially in patients with negative MRI studies during treatment. The risk of recurrent hyperprolactinemia with each millimeter increment in the size of the tumor remnant was 19 percent. However, until data from a study with a longer follow-up period are available, close monitoring for recurrent hyperprolactinemia and renewed tumor growth is important, particularly in patients with macroprolactinomas, in whom renewed growth may compromise vision.
Supported in part by a grant (2003068735) from the Italian Minister of University and Research, Rome.
We are indebted to Giovanni Vitale, Maria Luisa Landi, and Nicola Milano (Department of Molecular and Clinical Endocrinology and Oncology, Federico II University of Naples) for contributing to patients' care; to Francesco Briganti, Sossio Cirillo, and Francesco Di Salle (Department of Biomorphologic and Functional Sciences, Federico II University of Naples) for reading MRI studies of the sella; to Mario Petretta (Department of Internal Medicine, Federico II University of Naples) for his help in performing an accurate statistical analysis of the data; and to Edward Laws, Jr. (Department of Neurological Surgery, University of Virginia, Charlottesville), for his critical evaluation and linguistic revision of the manuscript.
Source Information
From the Departments of Molecular and Clinical Endocrinology and Oncology, Section of Endocrinology (A.C., A.D.S., C.D.S., R.P., G.L.), and Neurologic Sciences, Section of Neurosurgery (P.C.) — all at Federico II University of Naples, Naples, Italy.
Address reprint requests to Dr. Colao at the Department of Molecular and Clinical Endocrinology and Oncology, Federico II University, via S. Pansini 5, 80131 Naples, Italy, or at colao{at}unina.it.
References
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Related Letters:
Prolactinomas
Friedman T. C., Couldwell W. T., Weiss M. H., Laws E. R. Jr., Hortin G. L., Colao A., Lombardi G., Schlechte J.
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N Engl J Med 2004;
350:1054-1057, Mar 4, 2004.
Correspondence
This article has been cited by other articles:
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50 percent),