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Original Article |
Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham B15 2TH, United Kingdom
Address all correspondence and requests for reprints to: Prof. M. C. Sheppard, Division of Medical Sciences, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, United Kingdom. E-mail: . m.c.sheppard{at}bham.ac.uk
Abstract
Depot somatostatin analogs are now increasingly being prescribed as adjuvant and primary therapy for the treatment of acromegaly. Previous studies have shown them to be both effective and safe, suppressing GH levels to less than 2 µg/liter in 50–65% of cases and normalizing serum IGF-I levels in 65%. However, published data on their long-term efficacy and safety is scanty. We analyzed data from 22 patients (16 female and 6 male) treated with Sandostatin LAR or Lanreotide for an average of 41 months (range 12–89). Three patients had previously been treated with surgery, two with radiotherapy, and seven with both. Ten patients had received primary medical therapy. Mean pretreatment GH levels were 13.1 ± 3.4 µg/liter, and IGF-I levels were 592.9 ± 53.9 µg/liter. Results after 12 months of therapy indicated reduction in GH (3.2 ± 0.7 µg/liter; P < 0.0001) and IGF-I (321.9 ± 33.9 µg/liter; P < 0.001) concentrations, and this was sustained at latest follow-up. Using GH criteria (serum GH < 2 µg/liter), 46% of subjects achieved a cure at 12 months, and 36% achieved a cure long-term. Fifty-two percent achieved normal IGF-I values at 12 months, and 67% long-term. Mean fasting and 2-h plasma glucose concentrations were similar at latest follow-up and at 12 months to baseline values. Three patients developed impaired glucose tolerance within 12 months of treatment, one going on to develop frank diabetes mellitus. However, glucose tolerance improved in five patients. Five patients developed gallstones while on treatment. In summary, this study reports the long-term efficacy of the depot somatostatin analogs as either adjuvant or primary therapy. Although overall glucose tolerance did not change, the development of impaired glucose tolerance in three patients at a time when GH levels were not changing highlights the ongoing need to monitor the long-term safety of these preparations.
ACROMEGALY IS A RARE but disabling condition associated with reduced life expectancy caused almost invariably by a GH-secreting adenoma. The definition of a cure for acromegaly has been the subject of much debate, but recent studies suggest a mean GH level of less than 2 µg/liter (random or mean during a day profile) is associated with mortality rates similar to those found in the general population (1, 2, 3). Transsphenoidal surgery and/or radiotherapy are still considered the treatment of choice, but despite recent advances in both these forms of treatment, the overall surgical cure rate remains around 60%, and radiotherapy may take 5–10 yr to lower GH to an acceptable level (4). Somatostatin analogs have been used as an adjunct to surgery and/or radiotherapy, but they are increasingly being used as first line therapy in the treatment of acromegaly. Octreotide, a long-acting synthetic somatostatin analog, has been used to treat acromegaly for over 15 yr and since the mid-1990s, two slow-release depot preparations have been introduced: Sandostatin LAR (Novartis Pharmaceuticals) and Lanreotide LA (Ipsen Pharmaceuticals). Previous studies, most of which have been limited to 12 months of follow-up, have shown them to be both effective and safe, suppressing GH levels to less than 2 µg/liter in 50–65% of cases and normalizing serum IGF-I levels in 65% of cases (5, 6, 7, 8, 9). Published data on the long-term efficacy and safety of these depot analogs is scanty, however, and concerns have been raised about tachyphylaxis, tolerability, and side effects such as the development of gallstones and glucose intolerance. Against this background, we have analyzed outcomes in 22 patients treated with depot somatostatin analogs for up to 89 months.
Subjects and Methods
Patient population
Twenty-two subjects (16 females and 6 males) with active acromegaly, as determined by the presence of clinical signs and symptoms, failure of GH to suppress less than 1 µg/liter during a 2-h 75-g oral glucose tolerance test (OGTT) and raised serum IGF-I levels, were selected from a cohort of 31 subjects who had been treated with long-acting somatostatin analogs. Of the nine subjects who were excluded, six had been on treatment for less than 12 months, two had their treatment stopped after surgery, and one subject had treatment withdrawn after 10 months due to lack of efficacy. At presentation, 12 subjects had macroadenomas, and 7 had microadenomas. In two subjects, one with known ectopic GHRH secretion secondary to a bronchial carcinoid tumor, pituitary magnetic resonance imaging (MRI) scans were reported as normal, and one subject had an empty sella. All subjects were treated with either Sandostatin LAR (Novartis Pharmaceuticals, East Hanover, NJ) or Lanreotide (Ipsen Pharmaceuticals, Dublin, UK), and doses were titrated according to biochemical response. In total, 18 subjects were treated with Sandostatin LAR (2 with a dose of 20 mg every 6 wk, 11 with 20 mg every 4 wk, and 5 with 30 mg every 4 wk), and 4 were treated with Lanreotide (3 with 30 mg every 2 wk and 1 with 30 mg every 10 d). The mean age at the onset of treatment was 52 yr (range, 28–69 yr), and the mean duration of treatment was 41 months (range, 12–89 months). Three subjects had previously undergone surgery, two had received radiotherapy, and seven had been treated with both surgery and radiotherapy. Ten subjects were treated with primary medical therapy, having received no definitive treatment for their acromegaly in the past. The mean pretreatment GH level was 13.1 ± 3.4 µg/liter (range, 1.8–67.6) with serum GH less than 2 µg/liter in one subject (5%), and the mean serum IGF-I was 592.2 ± 53.9 µg/liter (range, 203.3–1074.2) with normal serum IGF-I levels in four subjects (18%).
Methods
Serum GH levels were measured by an in-house RIA in a central laboratory as previously described (5). Individual GH levels were obtained by using the mean of five values measured during a 2-h 75-g OGTT. Serum IGF-I was measured using a commercial kit developed by the Nichols Institute (San Juan, CA), with acid-ethanol extraction performed to remove IGF binding proteins, as previously described (5). Glucose tolerance was analyzed using basal and 2-h plasma glucose levels from samples taken during a 2-h 75-g OGTT. All subjects had ultrasound scanning of the gallbladder performed by the same radiologist basally and at least every 6 months. Pituitary MRI scans were performed basally and at regular intervals.
Statistical analysis
Measurements of GH, IGF-I, and plasma glucose are expressed as the mean ± SEM, and the Wilcoxon matched-pairs signed ranks test was used to assess the effect of treatment on biochemical parameters. A P value less than 0.05 was considered statistically significant.
Results
Serum GH and IGF-I concentrations
Mean serum GH in the group fell from 13.1 ± 3.4 µg/liter at baseline to 3.2 ± 0.7 µg/liter (P < 0.0001) after 12 months of treatment with a depot long-acting somatostatin analog (Fig. 1
). This reduction was sustained with long-term treatment, with the mean serum GH concentration at latest follow-up being 3.0 ± 0.4 µg/liter (P < 0.0001 vs. baseline). Figure 2 shows the course of GH levels in each individual subject with time. Using a serum GH less than 2 µg/liter, 46% of subjects achieved a cure at 12 months, and 36% at the end of follow-up.
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). Figure 4 shows the course of the mean serum IGF-I concentration of each individual subject with time. Fifty-two percent of subjects achieved a normal age- and sex-related IGF-I value 12 months after starting treatment, and 67% at latest follow-up.
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Glucose tolerance status was defined using the 1999 World Health Organization criteria for the diagnosis of impaired glucose tolerance (IGT) and diabetes mellitus (10). A fasting plasma glucose of at least 7.0 mmol/liter was considered abnormal. IGT was defined as a plasma glucose level between 7.8 and 11.1 mmol/liter, and diabetes mellitus was defined as a plasma glucose level of at least 11.1 mmol/liter measured 2 h after a 75-g oral glucose load. Mean 2-h OGTT values in the group were similar throughout at 8.5 ± 1.1 mmol/liter at baseline, 7.9 ± 0.9 mmol/liter after 12 months of treatment, and 7.3 ± 0.6 mmol/liter at latest follow-up (P = not significant). The corresponding figures for fasting plasma glucose levels were 5.8 ± 0.4 mmol/liter, 6.2 ± 0.6 mmol/liter, and 5.5 ± 0.2 mmol/liter, respectively. At baseline, six subjects had IGT, and two had diabetes mellitus. After 12 months of treatment, three subjects developed IGT, one of whom went on to develop diabetes mellitus. A further subject developed IGT at latest follow-up. However, glucose tolerance returned to normal in four subjects with IGT after 12 months of treatment, and in an additional one at latest follow-up.
Gallstones
All subjects had serial ultrasound scanning of the gallbladder performed by the same radiologist at baseline and at least every 6 months. One subject was found to have evidence of significant gallbladder wall thickening at baseline and underwent a laparoscopic cholecystectomy. Five subjects (23%) developed new gallstones during the study period, and one developed gallbladder sludge. In four subjects, gallstones developed 24–40 months after commencing treatment with long-acting somatostatin analogs and persisted throughout the study period, whereas in the remaining one subject gallstones were identified 2 months into the study period and steadily increased in number. The gallbladder sludge was identified 34 months after commencing treatment and did not progress to gallstones during the study period (52 months). Only one of these subjects developed symptoms related to cholelithiasis, requiring referral to a gastroenterologist.
Primary medical treatment
Of the 22 subjects, 10 (8 females and 2 males) received depot long-acting somatostatin analogs as primary therapy, having had no definitive treatment for their acromegaly in the past. The mean age at the onset of treatment was 58 yr (range, 45–69 yr), and the mean duration of treatment was 40 months (range, 12–76 months). Six subjects had microadenomas, one had a macroadenoma without suprasellar extension, and one had an empty sella. Pituitary MRI scans were reported as normal in two subjects. Mean serum GH in this group was 9.8 ± 3.7 µg/liter at baseline, falling to 2.6 ± 0.6 µg/liter (P < 0.01) after 12 months of treatment, and 3.2 ± 0.8 µg/liter at latest follow-up (Fig. 5). Fifty percent of subjects achieved a cure using GH criteria (as defined above) at 12 months, and 40% at latest follow-up. Mean serum IGF-I was 592.9 ± 74.7 µg/liter at baseline, falling to 276.4 ± 33.9 µg/liter (P = 0.001) and 279.5 ± 47.7 µg/liter at 12 months and at latest follow-up respectively (Fig. 6). Fifty percent of subjects achieved normal age- and sex-related IGF-I values at 12 months and 60% at latest follow-up. Mean 2-h OGTT values were similar at baseline (8.9 ± 1.9 mmol/liter), 12 months (9.1 ± 1.9 mmol/liter), and latest follow-up (7.8 ± 1.0 mmol/liter). Two subjects developed IGT after 12 months of treatment, one of whom went on to develop diabetes mellitus. At latest follow-up, glucose tolerance had returned to normal in two subjects with IGT at baseline. During the study period, one subject developed new gallstones (10%), and one developed gallbladder sludge.
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The primary aims of therapy in acromegaly should be to reverse the symptoms and signs of the disease, treat the underlying cause, prevent disease recurrence, and improve long-term survival (11). Lowering GH concentrations rapidly achieves symptomatic relief and improves patient well being. A universally accepted definition of a cure remains elusive, but there is now evidence that achieving GH levels of less than 2 µg/liter is associated with near-normal life expectancy (1), making this the aim of therapy wherever possible. Surgery via the transsphenoidal route with or without adjuvant radiotherapy is still considered the treatment of choice, but despite recent advances in both these forms of treatment and the fact that the surgical cure rate for microadenomas may approach 90% in the hands of an experienced pituitary surgeon, the overall surgical cure rate remains around 60% (12), and radiotherapy may take 5–10 yr to lower GH to an acceptable level (4). Radiotherapy has the additional disadvantage of failing to normalize GH secretion pulsatility so that serum IGF-I levels remain raised (13). Furthermore, such therapies are associated with a high incidence of hypopituitarism, which itself is associated with excess mortality (14, 15). These concerns have led to a re-appraisal of medical therapy for acromegaly, not just as an adjunct to surgery and radiotherapy, but for use as first line primary therapy.
Octreotide, a long-acting synthetic somatostatin analog with a half-life of 80–100 min, was first synthesized in 1982 (16) and has been used to treat acromegaly for over 15 yr. Administered as a sc injection three times daily, doses of 100-1500 µg/d have been shown to effectively suppress GH levels to less than 4 µg/liter in 22–45% of cases and normalize IGF-I levels in 50% of cases (17, 18) The impact of frequent daily injections on patient compliance and quality of life and the mounting evidence that continuous octreotide infusions are more effective than sc regimens (19) provided the impetus for the development of depot long-acting preparations. Since the mid-1990s, two slow-release depot preparations, Sandostatin LAR (Novartis Pharmaceuticals) and Lanreotide (Ipsen Pharmaceuticals), have been introduced with the aim of abolishing the need for multiple daily injections and improving patient compliance. Previous studies, some of them large multicenter trials, have shown both drugs to be effective and safe, suppressing GH levels to less than 2 µg/liter in 50–65% of cases and serum IGF-I levels to normal in 65% of cases (5, 6, 7, 8, 9). Published data on the long-term efficacy and safety of these depot analogs is scanty, however, with few reports extending beyond 3 yr, and concerns have been raised about tachyphylaxis, tolerability, and side effects such as the development of gallstones and glucose intolerance.
In this series, we have studied outcomes in patients treated with depot somatostatin-analog preparations for up to 8 yr. We observed a significant reduction in GH and IGF-I levels in the whole group after 12 months of therapy, and this was sustained at latest follow-up with no evidence for tachyphylaxis. At 36%, the number of patients achieving a cure using GH criteria at latest follow-up was lower than in previous studies, but 62% achieved normal IGF-I levels, similar to previously reported figures. Although most studies have shown no significant effect on glucose tolerance, one group reported raised glycosylated hemoglobin levels after 6 months of treatment in 7 of 49 patients with normal glycosylated hemoglobin levels at baseline (20). In our study, overall glucose tolerance did not change, but four patients with normal glucose tolerance at baseline developed IGT at a time when GH levels were either improving or static. New gallstone formation has been reported in up to 24% of patients treated with depot somatostatin analogs (7, 21, 22, 23), a figure that is confirmed in this study (23%). In most cases, gallstone formation occurred only after patients had been treated with long-acting somatostatin analogs for at least 24 months, and once identified they remained present for the duration of the study period. In keeping with previous studies, the incidence of symptomatic cholelithiasis was rare, with only one patient developing symptoms and requiring referral to a gastroenterologist. Although we did not set out to assess change in tumor size, all patients received serial pituitary MRI scans, and in no case was an increase in tumor size reported.
Despite the proven efficacy of somatostatin analog therapy in acromegaly and the limitations of surgery and radiotherapy, very few studies have assessed the use of these drugs as first line therapy. Using three times daily sc octreotide, in a retrospective analysis, Newman (24) found no significant difference in GH and IGF-I reduction between primary and secondary treatment groups, suggesting that octreotide may be a reasonable primary medical option under certain circumstances, provided the tumor does not threaten vision or neurological function. In our study, the subgroup of patients on primary medical therapy achieved similar levels of GH and IGF-I suppression compared with the group as a whole. Using GH criteria, 40% of subjects achieved a cure at latest follow-up, and 60% achieved normal IGF-I concentrations. These figures are similar to those observed in the whole group (36% and 62%, respectively). There was no statistically significant difference in GH levels between the primary and secondary treatment groups at baseline, after 12 months of treatment, or at latest follow-up and the same was true for IGF-I. The safety profile in the primary therapy group was no worse than in the group as a whole, with only one patient developing gallstones and no change in overall glucose tolerance. Interpretation of our results must take into account the fact that most patients in the primary therapy group had microadenomas on pituitary imaging, although there was no statistically significant difference in baseline GH and IGF-I levels between the two groups.
As with previous studies, we observed a discrepancy between the proportion of patients with normal GH levels and those with normal IGF-I levels. There is ongoing debate about the correlation (or lack thereof) between serum GH levels and serum IGF-I levels in individual patients treated for acromegaly, and a number of mechanisms have been proposed to explain these discrepancies. IGF-I is dependent on the pattern as well as the amount of GH secretion (25) and may be affected differently from GH by different treatment modalities. In addition, several nonGH-dependent factors and mechanisms contribute to the determination of serum IGF-I levels (26).
To conclude, our study has shown that long-term use of depot long-acting somatostatin analogs for the treatment of acromegaly is effective and safe, with the outcomes observed in short-term studies sustained over longer periods. There was no increase or worsening of the observed side effects and no increase in tumor size with long-term use, although the development of IGT in four patients at a time when GH levels were either improving or static highlights the ongoing need to monitor the long-term safety of these preparations. Our findings also support the mounting evidence that in a subgroup of patients in whom surgery is unlikely to result in a cure, long-term treatment with depot somatostatin analogs is a safe and effective option, provided the tumor does not threaten vision or neurological function.
Acknowledgments
We thank Ms. E. Baister of Novartis Pharmaceuticals and Ms. June Wooldridge of Ipsen Pharmaceuticals for the assistance they provided.
Footnotes
Abbreviations: IGT, Impaired glucose tolerance; MRI, magnetic resonance imaging; OGTT, oral glucose tolerance test.
Received November 30, 2001.
Accepted May 22, 2002.
References
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