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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 12 4598-4601
Copyright © 2007 by The Endocrine Society

Long-Term Efficacy and Safety of Combined Treatment of Somatostatin Analogs and Pegvisomant in Acromegaly

Sebastian J. C. M. M. Neggers, Maarten O. van Aken, Joop A. M. J. L. Janssen, Richard A. Feelders, Wouter W. de Herder and Aart-Jan van der Lely

Department of Internal Medicine, Erasmus University Medical Centre Rotterdam, 3000 CA Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: Sebastian J. C. M. M. Neggers, M.D., Erasmus University MC Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. E-mail: s.neggers{at}erasmusmc.nl.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Background: We previously reported the efficacy of a combined treatment of active acromegaly with both long-acting somatostatin analogs (SSA) and pegvisomant (PEG-V).

Objective: Our objective was to assess long-term efficacy and safety in a larger group of acromegalic patients after a period of 138 (35–149) wk [median (range)].

Design: PEG-V was added to high-dose SSA treatment in 32 subjects (13 females) who had not shown a normalization in serum IGF-I concentrations during SSA monotherapy. PEG-V dosage was increased until IGF-I concentration normalized. The maximal dose was 80 mg twice weekly.

Results: After dose finding, IGF-I remained within the normal range in all subjects with PEG-V administered once (n = 24) or twice (n = 8) weekly, on a total weekly dose of 60 (40–160) mg. Baseline IGF-I levels were positively correlated with the required dosage of PEG-V (r = 0.48; P = 0.006). PEG-V-dependent liver enzyme disturbances were observed in 11 (6 diabetic) subjects, of which symptomatic gallstones explained two cases. These liver enzyme disturbances were transient in all subjects without discontinuation or dose adaptation of PEG-V. In our series, diabetic patients had a 5.1 times (odds ratio) (confidence interval, 1.02–25.54; P < 0.05) higher risk for developing liver enzyme disturbances. These liver enzyme disturbances seemed to occur earlier. Pituitary adenoma size decreased in four patients. No increase in tumor size was observed in any of the patients.

Conclusion: Long-term combined treatment with long-acting SSA and (twice) weekly PEG-V for active acromegaly seems to be effective and safe. Patients with acromegaly and diabetes seem to have a higher risk of developing transient liver enzyme disturbances.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
THE CLINICAL MANAGEMENT of acromegaly has changed recently because optimal therapy has proven to reverse the increased mortality associated with acromegaly. Currently, transsphenoidal surgery (TSS) is still the treatment of choice for acromegaly, although in only 60% is an adequate biochemical remission or cure achieved. A chance on remission declines to less than 50% if a macroadenoma is present (1). Radiotherapy (RT), primary or postsurgically, is limited due to slow onset of effect and has a high occurrence of pan-hypopituitarism (2, 3, 4) and decreased quality of life (5). Nowadays, medical therapy plays an important role in controlling signs and symptoms of acromegaly, both as primary and secondary medical therapy. Long-acting somatostatin analogs (SSA) normalize IGF-I levels in two thirds of patients with acromegaly (6, 7, 8, 9, 10, 11). One of its side effects is the suppression of insulin secretion, which could lead to glucose intolerance (12, 13).

A more recent medical treatment modality is the GH receptor antagonist pegvisomant (PEG-V). With daily injections of PEG-V, in more than 90% of patients a normalization of IGF-I can be achieved (14, 15). In addition, glucose metabolism is improved (12, 14, 16, 17, 18). On the other hand, PEG-V has to be administered daily, and in some patients it was at least unable to prevent tumor growth (19). Combination of SSA and PEG-V treatment seems to be an attractive option because tumor suppression is combined with GH receptor blockade. We previously reported that PEG-V, administered weekly in addition to long-acting SSA therapy was able to normalize serum IGF-I levels in 95% of subjects (20). Here we present the long-term follow-up efficacy and safety data in the same patients plus newly included acromegalic subjects up to 138 (35–149) wk [median (range)].


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients

Patients were enrolled from a single center. All subjects [n = 32, 13 females; median age 52 (range 30–81) yr] had elevated IGF-I levels [56 (32–122) nmol/liter] despite 120 mg lanreotide Autogel (n = 22) or 30 mg octreotide LAR (10) monthly for at least 6 months before the start of this series. Baseline characteristics are presented in Table 1Go. In our series, patients with a pituitary macroadenoma and compression of the chiasm were not treated with a combination of SSA and PEG-V.


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  		TABLE 1. Baseline characteristics (n = 32)

 
Methods

All patients continued long-acting SSA therapy at monthly intervals and, on top of that, PEG-V was added weekly. Starting dose of PEG-V was 40 mg weekly. PEG-V dosage was adjusted until IGF-I was within the age-adjusted normal range. If IGF-I fell in the lowest quartile of normal, the PEG-V dosage was reduced. The intervals of dose adjustments were 6 wk until a controlled IGF-I was achieved twice. The subjects then visited our outpatient clinic every 12–16 wk. If a dose of at least 100 mg was required, patients divided the dosage in two (equal) parts and injected twice weekly.

IGF-I and other efficacy and safety data were assessed at these regular visits. Efficacy was assessed at the longest follow-up visit [138 (35–149) wk] for IGF-I, GH, glycosylated hemoglobin (HbA1c), fasting glucose, lipids, and a quality of life questionnaire, Patient-Assessed Acromegaly Symptom Questionnaire (15). IGF-I and GH concentrations were measured by immunometric assays (Diagnostic Products Corp., Los Angeles, CA). The IGF-I age-adjusted reference ranges were used (21).

Safety assessment included electrocardiogram, serum concentrations of alkaline phosphatase, {gamma}-glutamyltranspeptidase ({gamma}-GT), alanine aminotransferase (ALT), aspartate aminotransaminase (AST), lactate dehydrogenase, total bilirubin, and change in pituitary tumor volume. Tumor volume was assessed at baseline by magnetic resonance imaging, which was repeated every 6 months. Changes in pituitary tumor size were assessed by the same neuroradiologist.

Statistical analysis

Paired nonparametric data were analyzed with the Wilcoxon’s signed-rank test. The nonpaired data were assessed with the Mann-Whitney U test and cross-tables with the Fisher’s exact test. Statistical analyses of the data were performed by Prism version 5.00 for Windows (GraphPad Software, San Diego CA). Statistical significance was accepted at P < 0.05 (two-tailed). Data are expressed as median ± SD unless otherwise specified.


   Results
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 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Efficacy

Thirty-two patients with acromegaly were enrolled in this series. Normalization of serum IGF-I levels was achieved in all patients (Fig. 1Go). The median IGF-I decreased from 56.00 ± 28.7 nmol/liter at baseline, on SSA monotherapy, to a lowest level of 17.85 ± 6.16 nmol/liter (P < 0.0001) during combined treatment. The PEG-V dose needed for normalization of IGF-I was 60 (40–160) mg weekly [median (range)]. This median dose is identical to the one we reported previously (20). Eight patients needed PEG-V twice weekly.


Figure 1
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  		FIG. 1. IGF-I concentration in serum of 31 patients with acromegaly before (•) and after ({circ}) 138 (35–149) wk of combined therapy. Shaded area indicates age-dependent normal range for IGF-I.

 
The necessary dose of PEG-V for normalization of IGF-I was not significantly different in the primary medical therapy group (60.00 ± 43.27 mg) vs. the TSS group (55.00 ± 40.08 mg). A similar observation was made with regard to the diabetes mellitus (DM) group (55.00 ± 58.27 mg) vs. non-DM group (60.00 ± 32.70 mg). The necessary dose of PEG-V for normalization of IGF-I was positively correlated with baseline IGF-I levels, corrected for age (r = 0.48; P = 0.006) (Fig. 2Go).


Figure 2
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  		FIG. 2. The relation between baseline IGF-I and the necessary dose of PEG-V in a linear regression model. IGF-I is corrected for age by Z-score. r = 0.48; P = 0.006.

 
Metabolic control in patients with DM improved significantly after normalization of IGF-I during combined treatment. Nine of 10 DM patients had a significant decrease in HbA1c (P = 0.0156). Even after normalization of IGF-I, and with the same PEG-V dose, a further significant decrease in HbA1c could be observed (P = 0.0313) over a period of 6–18 months. In one patient, HbA1c could not be assessed because of hemoglobinopathy. Patients on insulin therapy (n = 7) had to decrease their insulin dosage, and one patient could stop insulin therapy and continued oral medication for DM. The remaining three patients did not change their insulin dosage, but still their HbA1c levels decreased.

Quality of life, compared with baseline, was improved in any assessment during follow-up (P < 0.05). IGF-I correlated well with quality of life.

Safety

Transient elevated liver enzyme tests (TLET) were observed in 11 patients (34%) (Table 2Go). Of these 11 subjects with TLET, six patients (55%) also suffered from DM. In our study, acromegaly patients with DM had a 5.1 times (odds ratio) (confidence interval, 1.02–25.54; P < 0.05) higher risk for developing TLET than nondiabetic subjects. We already reported on one diabetic patient who developed a transient drug-induced hepatitis due to which pegvisomant medication was stopped after 25 wk (22). Data of this patient are included in the safety data and baseline analyses. Subjects with DM also tended to have an earlier onset of TLET (21.0 ± 10.5 wk) than subjects without (25.0 ± 36.3 wk), although this was not significant (P = 0.178) (Fig. 3Go). The duration of the TLET was the same in both DM (12.0 ± 6.1 wk) and non-DM (18.0 ± 11.5 wk).


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  		TABLE 2. Clinical and biochemical characteristics of 11 patients with liver enzyme disturbances during combined therapy of SSA and PEG-V (twice) weekly

 

Figure 3
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  		FIG. 3. The interval between start of therapy and onset of transaminases abnormalities divided by acromegaly patients with (+) and without (–) DM. The individual subjects are shown as closed circles, and the line represents the median.

 
In two patients, gallstones, possibly related to long-term use of SSAs, could explain the TLET. Patient 8 (Table 2Go) was diagnosed as having cholecystitis and underwent cholecystectomy, after which TLET normalized rapidly. In patient 7, a magnetic resonance imaging scan of the liver revealed gallstones, and the TLET spontaneously disappeared without intervention. We concluded that in this patient, passage of a gallstone caused the TLET.

In 28 subjects, no increase in size of the pituitary tumor was observed. In four subjects (13%), a regression in tumor size by more than 25% occurred. None of these four patients had received RT before enrollment in this series, whereas three subjects (9%) were on primary medical therapy and had been treated for 43, 45, and 73 wk with monotherapy SSA and for 74, 148, and 143 wk with combination therapy. The other subject had TSS 2 yr before enrollment and had been treated for 71 wk with monotherapy SSA and 143 wk with combination therapy.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
We report here that long-term combined therapy of acromegalic patients with long-acting SSAs and PEG-V (twice) weekly is highly effective and safe. In all patients, IGF-I could be brought back within the age-adjusted reference range. Compared with the reported remission rates of long-acting SSAs of about two thirds of patients, the combination therapy seems superior. It is comparable with the efficacy of PEG-V daily administrations as monotherapy for acromegaly, which is considered to be more than 90% (14, 15). We observed that the (twice) weekly dose of PEG-V that is necessary for IGF-I normalization is equal to the one, we reported earlier (median, 60 mg; range, 40–160 mg) (20). Probably mainly because of the reduced levels of endogenous GH due to the SSA therapy, less PEG-V is needed to normalize serum IGF-I levels, because it meets less GH to compete for GH receptor binding. The necessary dose of PEG-V for normalization of IGF-I was associated with baseline IGF-I levels on monotherapy SSA. In previous studies with PEG-V monotherapy, such a relationship was not observed. The dose of PEG-V necessary for normalization of IGF-I did not differ between patients with primary medically treated patients and patients who previously underwent TSS (with or without RT). This is in contrast to studies on SSA monotherapy, showing that previous tumor debulking leads to a higher percentage of patients achieving biochemical remission with SSA (23).

In 11 patients (34%), we observed TLET. Two patients had TLET due to gallstones probably related to the use of long-acting SSAs (20). Liver enzyme disturbances during daily PEG-V treatment, AST, and ALT are usually more elevated than {gamma}-GT and bilirubin (24). The more prominent elevation in {gamma}-GT and bilirubin led to the conclusion that in two patients, the TLET was caused by cholelithiasis. The majority of patients who developed TLET had DM. These patients have an odds ratio of 5.1 to develop TLET during combination treatment and also tended to develop TLET earlier compared with patients without DM, although this was not significant. Another study assessed TLET in 12 patients with daily PEG-V of whom two subjects were cotreated with monthly long-acting octreotide (30 mg) (24). The liver enzyme disturbances were not dose related and occurred after 15.7 ± 10.7 wk (mean ± SD). However, no association of a phenotypic predictor was found. The mechanism of PEG-V-induced TLET remains unclear. The reason why the DM acromegalic patients in our series develop TLET earlier and more frequently also remains the subject of conjecture. We could not find another predictor that could explain the TLET. Although in our patients we did observe elevated liver enzyme tests, we consider the combined treatment as a safe treatment option of acromegalic patients that do not respond enough to monotherapy with SSA, because these mild disturbances of liver enzymes are transient without discontinuation or dose adaptation of PEG-V. This is in contrast to some other studies in which PEG-V is withdrawn. A frequent assessment of liver enzymes, as already indicated by the package insert of PEG-V, seems mandatory, however, especially in patients with DM.

In our series, we did not observe tumor growth in any of the patients. Four subjects even showed a regression in tumor size by more than 25%. It is noteworthy that none of these subjects were previously treated with RT.

From our clinical experience, one starts with a weekly dose of 40 mg PEG-V, which can be increased by 20 mg every 6 wk until normalization of IGF-I has been achieved. In our hands, we need two to three steps of dose titration to normalize IGF-I in the majority of patients, achieving disease control within 3 months after starting combination therapy.

In conclusion, although more research is necessary in larger cohorts of patients, our series indicates that long-term combined treatment of active acromegaly with both long-acting SSA and (twice) weekly injections of PEG-V seems to be effective and safe, at least for those subjects in whom serum IGF-I remains elevated during SSA monotherapy. Transient and mild elevations in liver functions were observed in one third of patients, and especially diabetic patients seemed to be more prone to this side effect.


   Footnotes
 
Disclosure Statement: W.W.d.H. and A.-J.v.d.L. are consultants for Novartis Pharma and received travel support from Novartis Pharma and Pfizer International. A.-J.v.d.L. is a consultant for Pfizer International and Ipsen Pharma International. The other authors have nothing to disclose. This series was not supported by an external funding source or pharmaceutical company.

First Published Online September 25, 2007

Abbreviations: ALT, Alanine aminotransferase; AST, aspartate aminotransaminase; DM, diabetes mellitus; {gamma}-GT, {gamma}-glutamyltranspeptidase; HbA1c, glycosylated hemoglobin; PEG-V, pegvisomant; RT, radiotherapy; SSA, somatostatin analogs; TLET, transient elevated liver enzyme tests; TSS, transsphenoidal surgery.

Received June 4, 2007.

Accepted September 13, 2007.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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