The efficacy of octreotide LAR in acromegalic patients as primary or secondary therapy

Abstract

Objective:

The objective of this study was to investigate the efficacy of octreotide therapy in acromegalic patients as primary or secondary therapy.

Methods:

Ten acromegalic patients diagnosed at the Endocrinology Clinic in Sarajevo (seven females and three males, mean age 55.2 ± 7.2 years, age range 40–65 years, five patients with microadenoma and five patients with macroadenoma) were treated with octreotide. Among them, 60% of patients were operated on and the majority of the procedures were performed transnasaly (90%). That group of patients had recidivism of disease (pituitary adenoma and acromegaly). The concentration of human growth hormone (HGH) and insulin-like growth factor 1 (IGF-1) was evaluated at 0, 6 and 12 months, while magnetic resonance imaging (MRI) was taken before the treatment and 12 months after. Eight patients received octreotide 30 mg/28 days, one patient received a dose of 20 mg and the other received 60 mg/28 days.

Results:

Before treatment growth hormone (GH) levels were 50.87 ± 10.56 ng/ml (range: 26–64.9), IGF-1 were 776.66 ± 118.40 ng/ml (range: 526–934). Four patients (40%) were treated with primary octreotide treatment and six patients (60%) with secondary somatostatin analog treatment. At the beginning of therapy, there were no differences in terms of age, HGH levels and IGF-1 levels between primary and secondary treatment groups (p > 0.05). The difference between groups was only in regard to the size of tumors (p = 0.01). After 6 and 12 months the GH levels decreased to 1.61 ± 0.86 ng/ml (range: 0.7–2.65) and 1.85 ± 2.40 ng/ml (range: 0.0–8.3), respectively, while the IGF-1 became 305.90 ± 43.19 ng/ml after 6 months of treatment (range: 240–376) and 256.99 ± 71.43 ng/ml after 12 months of octreotide treatment (range: 126–325), respectively. The pituitary adenomas size prior to treatment was 9.57 mm, while after 12 months of treatment, the size decreased to 8.0 mm. After therapy, a GH decrease to less than 2.5 ng/ml was achieved in 90% of cases; tumor size decrease was achieved in 60% while normalization of IGF-1 was achieved in 100% of the patients, respectively. All differences about HGH and IGF-1 in each group were statistically significant (p < 0.05). In the group of acromegalic patients treated with octreotide LAR as primary therapy, the difference was more significant for GH and IGF-1 than for adenomas size.

Conclusions:

Octreotide treatment of acromegaly not only decreases GH and IGF-1 concentrations, but also appears to diminish the size of the tumor in about 60% of cases. The somatostatin analogs are more efficient in the primary treatment of acromegalic patients, due to the fact that primary therapy is as effective as secondary therapy but primary therapy has small advantages when compared with secondary octreotide therapy because no surgical treatment is required before.

Background

Acromegaly is a chronic metabolic disorder in which there is too much growth hormone and the body tissues gradually enlarge. Acromegaly occurs in about 6 of every 100,000 adults [Melmed and Kleinberg, 2008]. In over 90% of acromegaly patients, the overproduction of growth hormone (GH) is caused by a benign tumor: adenoma of the pituitary gland [Giustina et al. 2000]. Treatment usually needs a combination of several treatment modalities to suppress the disease activity. Pituitary surgery, medical treatment with somatostatin analogs (SSAs) and radiotherapy have been the cornerstones in the management of acromegaly. Biochemical control of acromegaly is currently defined by the achievement of GH suppression after oral glucose tolerance test (OGTT) and of normal age- and gender-matched insulin-like growth factor 1 (IGF-1) levels. GH suppression was considered normal when the hormonal value fell to <1 ng/ml during OGTT [Melmed et al. 2002]. Drugs used to lower the production of growth hormone or block its action on target tissues include SSAs, growth hormone receptor antagonists (GHRAs) and dopamine agonists. Somatostatin is chemically unstable and broken down by the body within minutes of its release. Octreotide, in contrast, is very stable and, therefore, much longer acting. The main side effects of SSAs are gastrointestinal symptoms (diarrhea, abdominal pain and nausea), but these and other side effects occur primarily during the first month of treatment, with few cases occurring later in treatment. Other adverse reactions include gallstones, hypoglycemia or hyperglycemia, injection-site pain, transient hair loss and hypothyroidism [Melmed et al. 2002]. SSAs have become the mainstay of the medical treatment of acromegaly, with dopamine agonists and GHRAs as an alternative medication. SSAs are used according to whether recovery was not obtained after surgery or pituitary surgery was contraindicated. Numerous studies have demonstrated the efficacy of octreotide in the management of acromegaly. Studies have shown that octreotide results in a decrease in GH and IGF-1 levels in a majority of patients with normalization of IGF-1 levels in up to 60% of patients, indicating biochemical remission. Normalization of IGF-I level has been associated with a reduction of the excess mortality in acromegaly [Swearingen et al. 1998] and improvement in cardiac performance on octreotide [Colao et al. 2000]. Twelve months after first-line treatment with SSA or surgery, Coalo and colleagues found a similar improvement in left ventricular hypertrophy and diastolic filling. In contrast, systolic function improved more evidently in SSA-treated patients [Coalo et al. 2008]. Both a direct effect of SSA and a more preserved pituitary function might explain these results.

Another very important component of the efficacy of SSA therapy for acromegaly is its effect on tumor shrinkage. Tumor size reduction was most often reported to be between 20% and 50%. Tumor shrinkage data were available from trials in which approximately 90% of patients treated with octreotide LAR and about 10% of those treated with lanreotide SR were preselected for octreotide responsiveness. Most patients with acromegaly (75.5%) had 25% or greater tumor shrinkage after 12 months of primary SSA therapy: significant increase of tumor mass occurred in only 2.1% of patients (those uncontrolled during treatment). The best predictor of tumor shrinkage has been posttreatment IGF-I [Colao et al. 2006]. Most patients noted a marked improvement in their symptoms of acromegaly such as headaches, joint pains and diaphoresis very soon after starting octreotide therapy. An improvement in the signs and symptoms of acromegaly occurs in 64–74% of overall patients treated with depot analog therapy [Stewart et al. 1995].

Important, but somewhat controversial use of SSAs is as primary therapy for acromegaly. Overall, when the data from all analogs are combined, IGF-1 has been normalized in 60% of patients, and GH has been suppressed in 50% of patients who received primary SSA therapy [Colao et al. 1997; Biermasz et al. 1999; Newman et al. 1998].

There are a number of important considerations for the use of SSAs as primary therapy for acromegaly. Objectives for presurgical octreotide LAR therapy include: lower hormone secretion and relief of the symptoms of acromegaly, improvement of patients’ general condition for surgery, reduction of anesthesia risks, reduction of surgical complications and reduction time of postsurgery hospitalization. There is evidence that octreotide can soften the tumor tissue and make it easier to surgical dissection from normal pituitary tissue. It is important to also take into consideration that surgical outcome is correlated with the size and invasiveness of the tumor. The effect of primary therapy on tumor shrinkage is also clearly very important. Presurgical treatment with octreotide LAR as primary therapy has been shown to reduce the tumor volume and increase the chances for surgical cure [Colao et al. 1997]. Treatment of acromegalic patients with somatostatin analogs decreases HGH and IGF-1 concentrations, improves general and metabolic conditions and decreases morbidity and mortality in these patients [Cozzi et al. 2006]. The Acromegaly Consensus Group developed a consensus and provided recommendations on acromegaly management [Acromegaly Consensus Group, 2009]. Use of somatostatin receptor ligands (SRLs) is most appropriate in the following situations:

• - as first-line therapy when there is a low probability of surgical cure;

• - after surgery has failed to achieve biochemical control;

• - before surgery, in order to improve several morbidities that prevent or could complicate immediate surgery;

• - to provide disease control, or partial control, in the time between administering of radiation therapy and the onset of maximum benefit attained from radiation therapy.

Objectives of the Study

The objective of this study is to determine the effectiveness of octreotide LAR in treating acromegalic patients as primary or secondary therapy at a single center.

Methods

The study included a very small number of acromegalic patients diagnosed at the Endocrinology Clinic in Sarajevo (n = 10), 7 female and 3 male patients, mean age 55.2 ± 7.2 years, age range 40–65 years, 5 patients with microadenoma and 5 patients with macroadenoma. The patients have been thoroughly evaluated before treatment, and every following 6 months during the treatment which was applied for 1 year with octreotide. Each evaluation included clinical data, hormone testing and radiological (MRI) investigation. After signing the informed consent, acromegalic patients started the treatment with octreotide LAR. Somatostatin suppression tests (greater than 50% of the baseline value) were pursued before octreotide has been applied. All patients had active acromegaly. Among them, 60% of patients were operated on previously and in the majority of cases (90%) the procedure was performed transnasaly (90%). That group of patients had recidivism of disease (pituitary adenoma and acromegaly). Efficacy of octreotide LAR therapy was assessed by changes in mean GH and IGF-I serum concentrations, at months 0, 6 and 12. Tumor volume was assessed by contrast-enhanced MRI scan, taken at 0 and 12 months. At our center, this is the first time that octreotide LAR has been used as acromegaly treatment. Eight patients received sandostatin LAR 30 mg/28 days, one patient received 20 mg and one 60 mg/28 days. Normal IGF-1 serum concentrations for age and sex and a GH <2.5 ng/ml after oral administration of 100 g of glucose were defined as biochemical control. All research involving human subjects in this study had been performed in accordance with the ethical recommendations and practices of the Clinical Center, University of Sarajevo and the Declaration of Helsinki 1975, revised at Hong Kong 1989.

Statistical data analysis includes basic statistics, descriptive statistics and nonparametric statistics (Friedman, Wilcoxon signed ranks test and Mann–Whitney U-test). Statistical significance was set as p < 0.05.

Results

Before treatment mean concentrations of GH were 50.87 ± 10.56 ng/ml (range: 26–64.9 ng/ml), IGF-1 were 776.66 ± 118.40 ng/ml (range: 526–934 ng/ml); see Table 1. Four patients (40%) were followed with primary and six patients (60%) with secondary SSA treatment. At beginning of therapy between primary and secondary treatment groups had no differences in terms of age, HGH levels and IGF-1 levels (p > 0.05, Mann–Whitney U-test). Difference between groups was only with regards to the size of tumors (p = 0.01, Mann–Whitney U-test).

Table 1.

The level of HGH, IGF-1 and size of pituitary adenomas before, after 6 and after 12 months Sandostatin LAR treatment (total, primary and secondary therapy)

	group	n	HGH (ng/ml)	IGF-1 (ng/ml)	Size of adenoma (mm)
Before treatment	total	10	50,87	777,60	9,57
	primary	4	53,52	807,75	4,18
	secondary	6	49,10	757,50	13,17
After 6 months of treatment	total	10	1,61 (a)***	305,90 (a)***
	primary	4	1,36 (a)*	292,50 (a)*
	secondary	6	1,77 (a)**	314,83 (a)***
After 12 months of treatment	total	10	1,85 (a)***	256,99 (a)***	8 (b)**
	primary	4	1,0 (a)*	238,0 (a)*	2,88 (b)
	secondary	6	2,41 (a)**	269,65 (a)***	11,41 (b)*

a - Friedman test; b - Wilcoxon Signed Ranks Test

^*p<0.05

^**p<0.01

^***p<0.005

After 6 and 12 months the mean value of GH concentration decreased to 1.61 ± 0.86 ng/ml (range: 0.7–2.65 ng/ml) and 1.85 ± 2.40 ng/ml (range: 0.0–8.3 ng/ml), respectively (Figure 1). The difference between GH level before, after 6 months and after 12 months of octreotide treatment was statistically significant (Friedman test, p = 0.000) . Wilcoxon signed ranks test established a significant difference between GH before treatment and GH after 6 months treatment (p = 0.005) and insignificant difference between GH level after 6 months and GH after 12 months of treatment (p = 0.169). The mean values of IGF-1 became 305.90 ± 43.19 ng/ml after 6 months treatment (range: 240–376 ng/ml) and 256.99 ± 71.43 ng/ml after 12 months of octreotide treatment (range: 126–325 ng/ml), respectively, the difference between IGF-1 level before, after 6 months and after 12 months of octreotide treatment was statistically significant (Friedman test, p = 0.000) (Figure 2). Wilcoxon signed ranks test established a significant difference between IGF-1 before treatment and IGF-1 after 6 months treatment (p = 0.005) and between IGF-1 level after 6 months and IGF-1 after 12 months of treatment, respectively (p = 0.028).

Figure 1.

The effects of octreotide LAR on GH as primary and secondary therapy

Figure 2.

The effects of octreotide LAR on IGF-1 as primary and secondary therapy

Prior to treatment the mean size of the pituitary adenomas was 9.57 mm (min 3.0; max 20), while after 12 months of octreotide administration, the respective mean size has been observed to decrease to: 8.0 mm (min 1.0; max 18.0); see Figure 3. Wilcoxon signed ranks test established significant difference between adenomas size before treatment and adenomas size after 12 months treatment (p = 0.004).

Figure 3.

The effects of octreotide LAR on size of pituitary adenomas after 12 months treatment

After octreotide LAR therapy, decrease of GH below 2.5 ng/ml were achieved in 90% patients, decrease in the tumor size was achieved in 60% while normalization of IGF-1 was achieved in 100% of the cases, respectively. One of the patients with macroadenoma used 60 mg octreotide LAR as secondary therapy after surgical treatment because a dose of 30 mg was not enough to decrease GH and IGF-1.

All differences about HGH and IGF-1 in each group were statistically significant (p < 0.05), Table 1. In the group of acromegalic patients treated with octreotide LAR as primary therapy, the difference was more significant for GH (Friedman test, p = 0.018; reduction for −52.52 ng/ml) and IGF-1 (Friedman test, p = 0.039; reduction for −569.75 ng/ml) than for adenomas size (Wilcoxon signed ranks test, p = 0.06). These results of statistical tests may be explained with very small number of patients. After 6 months of octreotide treatment as primary therapy, GH reduced from 53.52 to 1.36 ng/ml and after 12 months reduced to 1.0 ng/ml, while IGF-1 reduced from 807.75 to 292.50 ng/ml after 6 months and to 238 ng/ml after 12 months of treatment. Adenomas size after 12 months of octreotide treatment as primary therapy reduced from 4.18 to 2.88 mm (reduction of 31%).

After 6 months of octreotide treatment as secondary therapy, GH reduced from 49.10 to 1.77 ng/ml and after 12 months reduced to 2.41 ng/ml (Friedman test, p = 0.009, reduction of −46.69 ng/ml) while IGF-1 reduced from 757.5 to 314.83 ng/ml after 6 months of therapy and to 269.65 ng/ml after 12 months of therapy (Friedman test, p = 0.002; reduction of −487.8 ng/ml). Adenoma size after 12 months of octreotide treatment as secondary therapy reduced for 13%, from 13.17 to 11.41 mm (Wilcoxon signed ranks test, p = 0.024).

Mann–Whitney U-test showed no difference between primary and secondary ocreotide treatment for GH and IGF-1 reduction (p > 0.05), while for adenomas, size reduction showed a difference (p = 0.01) which is similar to the difference before treatment. All of these findings lead to the conclusion that the primary therapy is as effective as secondary therapy but primary therapy has small advantages compared with secondary octreotide therapy because no surgical treatment is required.

Discussion

The therapeutic goals in acromegaly are to eliminate morbidity and to reduce mortality to the expected age- and sex-adjusted rates by using safe treatments that remove the tumor mass or control its growth and restore GH secretion and activity to normal levels. Surgery is the current first choice of therapy in terms of the treatment of the tumor mass.

Our study shows that octreotide LAR successfully controls GH and IGF-1 levels in patients with acromegaly, independently of whether it was applied as primary or secondary therapy. After application of octreotide LAR therapy, a decrease of GH levels below 2.5 ng/ml was achieved in 90% patients, while normalization of IGF-1 levels was achieved in 100% of the patients.

In a retrospective study [Cozzi et al. 2003] of prolonged octreotide LAR treatment as adjuvant treatment and as primary treatment; naive or previous pharmacotherapy, GH fell to less than 2.5 µg/l in 72% of patients and to less than 1 µg/l in 27% (p < 0.0001). Primary treatment and adjuvant treatment patients achieved similar final GH levels and rates of normalization. A progressive increase in the rate of normalization was seen during the study (GH levels below 2.5 µg/l achieved by 54% at 12 months, 62% at 24 months and 73% at 36 months). Normal age-matched IGF-I levels were reached in 75%. A progressive increase in the rate of normalization was seen during the study (normal IGF-I levels achieved by 61% at 12 months, 68% at 24 months and 79% at 36 months). Octreotide LAR controls GH and IGF-1 in 50–80% of patients with acromegaly [Colao et al. 2008]. It induces tumor shrinkage of >25% in >70% of patients during the first year of therapy. Treatment of >2 years results in median tumor shrinkage of >50%. Twelve months of treatment with octreotide LAR results in similar biochemical control to that seen after surgery. Octreotide is the most widely used medical treatment for acromegaly; it is effective in more than 50% of cases, is well tolerated and has high compliance rates based on monthly intramuscular injections.

Tumor shrinkage is an emerging feature of SSA treatment. Our results showed that in 12 months of octreotide LAR therapy, a decrease in the tumor size was achieved in 60% of the cases. SSA therapy is associated with tumor shrinkage in a significant proportion of patients with acromegaly.

Many studies have found changes in tumor size, measured as an end point for the long-acting SRL formulation, octreotide LAR. In many patients with acromegaly, simply preventing further tumor growth, and thus future mass complications, is a useful treatment outcome. It is therefore helpful to look at the percentage of patients who experienced no further tumor growth during SRL therapy [Cozzi et al. 2003; Bevan et al. 2002; Colao et al. 2001].

Some studies reported patients with continued tumor growth. Abe and Lüdecke found that 6 of 90 patients treated with octreotide subcutaneous for 4–6 months showed tumor growth [Abe and Lüdecke, 2001]. All six were invasive tumors, and maximum tumor diameter increased by a mean of 6.8 mm (range, 3–17 mm); notably, none of these cases had shown any fall in GH/IGF-I with octreotide treatment.

Lucas and colleagues found an increase of greater than 20% in tumor volume in 13 of 73 patients treated per protocol with lanreotide SR for 1–3 months [Lucas et al. 2003]. However, the majority of patients in this study were treated for only 1 month, so the apparent increases in tumor size may have been due to difficulties with accurate tumor measurement.

One of patients with macroadenoma in our study used 60 mg octreotide LAR as secondary therapy after surgical treatment, because a dose of 30 mg was not enough to decrease the level of GH and IGF-1.

A 24-week prospective, multicenter, randomized, open-label trial [Giustina et al. 2009] conducted from 12 December 2005 to 23 October 2007 in patients with persistently uncontrolled acromegaly despite ≥6 month conventional SSA therapy. Significantly, more patients achieved week 24 IGF-1 reduction in the high-dose than the high-frequency group (p < 0.05). In the high-dose group only, week-24 IGF-1 values were significantly reduced (p = 0.02) versus baseline. Normalization of IGF-1 levels occurred only with the high-dose regimen (p = 0.02). High-dose octreotide treatment is safe and effective (normalization of IGF-1 levels) in a subset of patients with active acromegaly inadequately controlled with long-term SSA. Individualized octreotide doses up to 60  mg/28 days may improve the outcomes of SSA therapy.

Conclusion

Octreotide LAR treatment of acromegalic patients not only decreases HGH and IGF-1 concentrations, but also appears to diminish the size of the tumor. The SSAs are more efficient in primary treatment of acromegalic patients, due to the fact that primary therapy is as effective as secondary therapy, but primary therapy has a small advantage when compared with secondary octreotide therapy because no surgical treatment is required.