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Original Studies |
Department of Medicine, New York University and Veterans Administration Medical Center (C.B.N., D.L.K.), New York, New York 10010; the Division of Endocrinology and Metabolism, B-131 Cedars-Sinai Medical Center (S.M.), Los Angeles, California 90048; the Department of Radiology, New York University Medical Center (A.G., M.D.), New York, New York 10016; the Department of Radiology, Hospital of the University of Pennsylvania (D.T.), Philadelphia, Pennsylvania 19104; Endocrinology Division, University of Pennsylvania School of Medicine (P.S.), Philadelphia, Pennsylvania 19104-6149; the Department of Medicine, Mayo Clinic (W.Y.), Rochester, Minnesota 55905; the Neuroendocrine Unit, Massachusetts General Hospital (A.K.), Boston, Massachusetts 02114; the Center for Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Medical School (M.E.M.), Chicago, Illinois 60611; the Section of Endocrinology, University of Texas M. D. Anderson Cancer Center (R.G.), Houston, Texas 77030; Innova Medical Services (L.S.), Brooklyn, Ohio 44144; the Division of Endocrinology, Diabetes and Clinical Nutrition, Oregon Health Sciences University (D.C.), Portland, Oregon 97201; the Department of Medicine, Ohio State University Medical Center (W.M.), Columbus, Ohio 43210; the Department of Medicine, Brown University-Rhode Island Hospital (I.J.), Providence, Rhode Island 02903; the Department of Medicine, University of Virginia Medical Center (M.L.V.), Charlottesville, Virginia 22908; the Department of Medicine, University of Michigan Medical Center (A.B.), Ann Arbor, Michigan 48109-0354; and the Department of Medicine, University of Illinois (L.F.), Chicago, Illinois 60612
Address all correspondence and requests for reprints to: David L. Kleinberg, M.D., Department of Medicine, New York University and Veterans Affairs Medical Center, 423 East 23rd Street, 16043 West, New York, New York 10010.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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In the second phase of the study, in which patients were randomized to either 100 or 250 µg octreotide, three times daily, mean integrated GH and IGF-I concentrations after 3 and 6 months were equivalent in the primary and secondary treatment groups. During long term open label treatment, mean GH fell from 32.7 ± 5.2 to 6.0 ± 1.7 µg/L 2 h after octreotide injection in the primary therapy group and remained suppressed for a mean period of 24 months (range, 3–60 months). The mean final daily dose was 777 µg. In the patients receiving secondary treatment, mean GH fell from 30.2 ± 7.6 to 5.6 ± 1.1 µg/L after 3 months and remained suppressed for the remainder of the study (average dose, 635 µg daily). Mean IGF-I concentrations fell from 5.2 ± 0.5 x 103 U/L (primary treatment group) and 4.7 ± 0.4 x 103 U/L (secondary treatment group) to a mean of 2.2 ± 0.3 x 103 U/L in both groups after 3 months of open label treatment and remained suppressed. IGF-I was reduced into the normal range during at least half of the study visits in 68% of the primary treatment group and in 62% of the secondary treatment group.
Patients whose GH levels fell to at least 2 SD below the baseline mean GH were considered responders. There was no significant difference in the percentage of responders in the primary and secondary treatment groups (70% vs. 61%), nor was there a statistical difference in the mean GH concentrations between the groups.
Symptoms of headache, increased perspiration, fatigue, and joint pain were reported at baseline by 46%, 73%, 69%, and 85%, respectively, of patients in the primary therapy group and improved during 3 yr of octreotide treatment in 50–100%. Similarly, these acromegaly-related symptoms were reported by 62%, 58%, 78%, and 60% of patients in the secondary therapy group, and improvement was noted in 62–88%.
Pituitary magnetic resonance imaging scans were available in 13 of 26 patients in the primary treatment group before and after 6 months of octreotide treatment. Tumor shrinkage was observed in 6 of 13 patients, with reduction in tumor volume greater than 25% in only 3. Of 6 patients with documented tumor shrinkage, IGF-I was reduced into the normal range in 4 patients. Of the 7 remaining patients in whom tumor shrinkage was less than 10%, IGF-I was reduced into the normal range in 5 patients. The degree of tumor shrinkage did not correlate with the percent reduction in IGF-I or GH.
In summary, octreotide was equally effective in 26 previously untreated acromegalic patients (primary treatment group) and 81 patients previously treated with either surgery or pituitary radiation (secondary treatment group). These observations call into question the current practice of surgical resection of all newly diagnosed GH-secreting pituitary adenomas regardless of the likelihood of cure. Although surgery is the treatment of choice in patients with tumors likely to be completely resected, our results suggest that if the possibility of surgical cure is low, as in patients with large or invasive tumors, then octreotide may be a reasonable primary therapeutic modality provided that the tumor does not threaten vision or neurological function.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Surgical resection of the pituitary adenoma is still considered the treatment of choice for acromegaly, even though the surgical cure rate is relatively low (3, 4, 9, 10, 11). Pituitary adenomectomy, in the hands of experienced neurosurgeons, fails to cure as many as 50–60% of patients (9, 10, 11, 12, 13). The cure rate is higher in patients with microadenomas, but lower in those with macroadenomas, which represent the majority of GH-secreting pituitary tumors (10, 12, 13). Therefore, many patients who undergo initial surgery require additional therapy, such as radiation, somatostatin analogs, or dopamine agonists, to alleviate potentially disabling signs and symptoms, and reduce GH and IGF-I levels to normal. Assuming that overall mortality is reduced when GH levels in patients with acromegaly are lowered to below 2.5 µg/L, as has been shown by Bates et al. (14), we anticipate that reduction of GH to normal will prevent or delay cardiovascular, cerebrovascular, and neoplastic sequelae of acromegaly (15, 16, 17).
Several studies in which newly diagnosed acromegalics were given octreotide preoperatively for short time periods of time before surgery have found reductions in GH and IGF-I levels and variable effects on tumor size (6, 18, 19). Studies of prolonged release somatostatin analogs have also included small numbers of patients who had not undergone pituitary surgery or irradiation (20, 21, 22). Despite these reports, the efficacy of octreotide as primary therapy for acromegaly has not been adequately demonstrated. To determine whether primary therapy of acromegaly with octreotide is effective long term, we compared the effects of octreotide in 26 previously untreated acromegalic patients (primary treatment group) with those in 81 patients who had been initially treated with surgery and/or pituitary radiation (secondary treatment group). These patients were part of a multicenter study, and 2 previous reports have been published on the results in the group as a whole (1, 2). In the present report, effects on GH, IGF-I, clinical symptoms, and tumor size were compared between the primary and secondary treatment groups.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Patients were studied at 14 medical centers. All patients had active acromegaly, as determined by failure to suppress GH levels below 2 µg/L during a 2-h oral glucose tolerance test. Twenty-six patients (10 men and 16 women, mean age 50 yr; range, 20–78 yr) had not received prior treatment, whereas 81 patients (43 men and 38 women; mean age, 44.8 yr; range, 17–85 yr) had previously been treated with surgery and/or radiotherapy at least 1 yr before entry into the study. Of the 81 previously treated patients, 46 had been treated only with surgery, 27 had been treated with surgery and radiation, and 8 had been treated with radiation alone. The experimental protocol was approved by the institutional review boards of each medical center, and each patient gave written informed consent.
Study design
The study was divided into 3 phases. After an initial 2-month double blind, placebo-controlled phase, patients were randomized to treatment with either 100 or 250 µg octreotide, sc, every 8 h for 6 months (1). Thereafter, in the third phase of the study, octreotide was reinitiated at a dose of 100 µg, sc, every 8 h and subsequently increased at the discretion of each investigator to improve each patient’s individual response, which included improvement in symptoms and signs of acromegaly as well as reduction in GH and IGF-I into the normal range (2). The maximum dose allowed during the first 3 months of the open label phase of the study was 250 µg, sc, every 8 h. Thereafter, further increments or decrements in octreotide dosage were permitted so that the final dose ranged between 100-1750 µg daily.
GH and IGF-I measurements
During the second phase of the study in which patients were randomized to either 100 or 250 µg octreotide, three times daily, GH levels were determined in samples taken hourly between 0800–1600 h at baseline, after 3 and 6 months of octreotide treatment, and 4 weeks after the end of treatment. Octreotide was injected after the first blood sample had been drawn. Serum GH levels were measured by RIA at Nichols Institute (San Juan Capistrano, CA). The area under the curve was divided by 8 to obtain an integrated mean GH concentration. Plasma was pooled at 0, 4, and 8 h for the measurement of IGF-I. IGF-I was measured by direct RIA at Nichols Institute. Although this method does not exclude IGF-binding proteins, relative changes in IGF-I can be determined, and measurements of IGF-I by unextracted assays have been shown to correlate with measurements obtained by assays involving extraction of binding proteins (1). In this assay, the normal range is not adjusted for age. The normal range for IGF-I is 0.4–2.2 x 103 U/L in adult women and 0.4–1.9 x 103 U/L in adult men.
During the next phase of the study (open label), serum GH and plasma IGF-I concentrations were measured at baseline and during treatment 2 h after the injection of octreotide. The 2 h point was chosen because it represents the nadir of GH levels after octreotide administration. The mean treatment period was 39 months and ranged from 6 months to 5 yr.
Symptoms of acromegaly
At each visit, patients were asked to rate symptoms of acromegaly (headache, increased perspiration, fatigue, and joint pain) on a five-point scale where 0 = not present, 1 = mild, 2 = moderate, 3 = severe but not incapacitating, and 4 = severe and incapacitating. Adverse events were also recorded and have been reported previously (2).
Magnetic resonance imaging (MRI)
Pituitary MRIs taken at baseline and after 6 months of treatment in 13 patients in the primary treatment group (11 with GH-secreting macroadenomas) were evaluated retrospectively. MRI scans were performed at 7 study centers using a variety of scanners. Transaxial, sagittal, and coronal views were reviewed as available.
Two methods of analysis were attempted, an objective assessment of tumor volume and a subjective side by side comparison of the films. For the objective assessment, selected hard copy images of the pituitary region were digitized. The tumor outlines were traced using a bitpad. Interslice gaps and magnification factors were entered into the program. For this method variability was high, and interobserver reliability was low. This was attributable to differences in quality of the MRIs, the variability of the scanning equipment used at multiple centers, and errors inherent in the method.
In the subjective assessment, the results of which are reported here, pretreatment and posttreatment scans were evaluated by two radiologists in side by side comparisons. The observers were blinded to the dates of the scans. Pituitary tumor size was evaluated by comparing sagittal to sagittal, coronal to coronal, and transaxial to transaxial views. The percent change in the size of the tumor was estimated. The minimal change detectable was 10%. The results of the two observers were averaged and collapsed into a four-point scale: less than 10%, 10–25%, 25–50%, and more than 50% reductions in tumor size.
Statistical analysis
Measurements of GH and IGF-I are expressed as the mean ±
SEM. To assess differences in response to octreotide
treatment between previously treated and untreated patients, we used
ANOVA for comparing either GH or IGF-I concentrations, implemented with
the JMP statistical package (SAS Institute, Cary, NC). In the ANOVA we
took into account the correlation of measurements taken at different
times within each subject. To compare the percent GH reduction (to 
2
µg/L) in previously treated vs. untreated subjects, we
used Pearson’s 
2 statistic. In some analyses the
cross-tabulations were based on the number of time points after the
baseline at which the GH level was 2 µg/L or less. The relationship
between tumor shrinkage and percent reductions in GH and IGF-I was
determined by calculation of the Spearman rank correlation
coefficient.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Figure 1
depicts mean serial GH
levels measured at hourly intervals between 0800–1600 h during the
dose comparison phase of the study in 23 patients in the primary
treatment group and 77 patients in the secondary treatment group. These
measurements were performed the day before initiation of octreotide and
at 6 months of treatment with either 100 or 250 µg octreotide three
times daily. The mean octreotide dose was 593 µg daily in the primary
treatment group and 513 µg daily in the secondary treatment group. In
the primary treatment group, mean GH fell from 21.5 ± 0.4
(±SEM) µg/L to a nadir of 7.2 ± 2.6 µg/L 2
h after octreotide injection and remained suppressed for up to 6 h
postinjection. In the secondary treatment group mean GH levels fell
from 30.4 ± 10.1 to 7.1 ± 1.4 µg/L 2 h after
octreotide injection. There was no statistically significant difference
in baseline GH levels or treatment GH levels between the primary and
secondary treatment groups. However, the percent reduction in GH from
pretreatment levels was significantly greater in the primary treatment
group (P < 0.0001).
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. Although previously untreated patients
had slightly higher baseline integrated GH levels than previously
treated patients, neither the baseline GH levels nor the GH and IGF-I
concentrations after 3 and 6 months of treatment were different. In
patients receiving octreotide as primary therapy, mean integrated GH
levels after 6 months were 13.2 ± 4.8 µg/L in 8 patients
randomized to 100 µg octreotide and 11.4 ± 3.7 µg/L in 15
patients randomized to 250 µg octreotide. These GH concentrations
were not statistically different.
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. In previously untreated patients
taking octreotide for a mean period of 34 months (range, 3–60 months),
mean GH fell from 32.7 ± 5.4 µg/L at the end of the washout
period to 6.6 ± 1.7 µg/L (2 h after octreotide injection) after
3 months of open label treatment and remained suppressed for the rest
of the study. In previously treated patients, mean GH fell from
30.2 ± 7.6 to 5.6 ± 1.1 µg/L at the same time point. Mean
GH levels during treatment were not different between the two groups.
Although the secondary treatment group had a higher mean GH level at
one of the time points (1 yr), this difference was not statistically
significant (P = 0.43). Forty-three percent of patients
in the primary treatment group compared with 22% in the secondary
treatment group had GH values of 2 µg/L or less during at least four
study visits (P = 0.06).
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). IGF-I values before and during
treatment were not statistically different between the two groups. Of
25 previously untreated patients with elevated baseline IGF-I levels,
IGF-I was reduced to normal during at least half of the study visits in
17 patients (68%). In 71 patients in the secondary treatment group,
IGF-I concentrations decreased to normal in 62%.
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). There was no
statistically significant difference in either the percentage of
responders in the primary and secondary treatment groups or in the mean
GH concentrations of the responders. Table 1 also shows the percentage
of patients in each group who had IGF-I levels reduced into the normal
range. There was no significant difference in IGF-I response in the
primary and secondary therapy groups.
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In 26 previously untreated patients, symptoms of headache,
increased perspiration, fatigue, and joint pain were present at
baseline in 12 (46%), 19 (73%), 18 (69%), and 22 (85%) patients,
respectively. In 77 patients who had undergone surgery and/or pituitary
radiation, headache, increased perspiration, fatigue, and joint pain
were reported by 48 (62%), 45 (58%), 60 (78%), and 46 (60%),
respectively, before beginning octreotide. As shown in Table 2, symptoms improved in the majority of
patients during octreotide treatment. These results are limited by the
fact that we did not have a placebo group during long term
treatment.
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In 13 patients in the primary treatment group, MRI studies
performed at baseline and 6 months after the initiation of octreotide
therapy were reviewed by 2 different radiologists who were blinded to
the date of the studies and to patient identification. According to an
accepted measure of the extent of agreement beyond that expected by
chance alone, 
(23), there was agreement between the two
radiologists ( = 0.54). The probability that such agreement was due
to chance alone was very small (P = 0.001). Table 3 shows the percent change in tumor size
(which represents an average of the individual readings) and IGF-I and
GH levels at baseline and after 6 months of treatment. A reduction of
tumor size by at least 10% was observed in 6 patients. Tumor shrinkage
was greater than 25% in only 3 patients.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In a relatively small series, Bates et al. reported that the mortality rate in 48 acromegalics with GH levels below 5.0 µg/L was significantly greater than that in the general population (14). However, in 31 patients with GH levels below 2.5 µg/L, the mortality rate was not statistically different from that in the general population. Unfortunately, successful surgical excision of GH-secreting pituitary adenomas fails to cure the majority of patients, particularly those with a macroadenoma. These patients therefore require additional treatment postoperatively. Patients treated postoperatively with radiation also require long term treatment with somatostatin analogs because of the long delay in GH reduction. Although pituitary radiation is known to significantly lower GH over time (4), the efficacy of conventional radiation therapy in the treatment of acromegaly has recently been questioned (24). In 36 acromegalic patients treated with radiation postoperatively and 2 patients who were irradiated as primary therapy, mean plasma GH fell to 4.6 µg/L, but only 2 patients achieved normal age- and sex-adjusted IGF-I concentrations (while off medical therapy) during a mean follow-up period of 6.8 yr (24).
Somatostatin analogs are the most effective medications with which to treat acromegaly (25, 26) and are superior to dopamine agonists in reducing GH and IGF-I. However, formal comparisons of somatostatin analogs and dopamine agonists have only been made in a small number of patients (4, 27). Octreotide is well tolerated, with the most common side-effect being the development of gallbladder stones in 24% of patients (2). Despite the proven efficacy of octreotide and the limitations of surgical and radiation treatment, there is little information on the use of octreotide as first line treatment. In this study, primary treatment with octreotide was as effective in reducing GH and IGF-I to normal in 26 previously untreated acromegalic patients as it was in 81 patients not cured by surgery or pituitary radiation. IGF-I levels decreased to normal in 68% of the previously untreated patients and in 62% of patients previously treated with surgery and or radiotherapy.
The usefulness of octreotide as primary therapy for acromegaly is clearly limited by its minimal effect on tumor size. Only 3 of 13 patients had more than a 25% reduction in tumor size after 6 months of octreotide treatment. This contrasts with the earlier findings of Barkan et al., who reported tumor shrinkage ranging between 20–54% in 10 acromegalic patients with macroadenomas who were treated with octreotide preoperatively for 3–30 weeks (6). In contrast, in 25 acromegalics treated with octreotide for 4–39 months before surgery, greater than a 20% reduction in tumor size occurred in only 4 patients (18). Stewart and colleagues reported that in 2 patients with a microadenoma (computed tomography scan), there was no tumor visible (by MRI) after 12 months of treatment with the longer acting octreotide analog, sandostatin-LAR (20). Others, however, have reported more modest tumor shrinkage (>20%) in 4 previously untreated patients receiving sandostatin-LAR (22). Another long acting analog of somatostatin, slow release lanreotide, has also been shown to reduce tumor volume by at least 25% in 3 of 12 patients with GH-secreting macroadenomas (21). The development of more specific and more potent somatostatin analogs may result in more pronounced tumor shrinkage. Unfortunately, in the present study, there was little correlation between the effects of octreotide on GH and IGF-I and tumor shrinkage. Therefore, when octreotide is selected as primary therapy, attention must be paid to tumor size as well as to biochemical parameters during long term treatment.
Interpretation of our results must take into account the fact that patients who entered this study were not randomized to primary therapy with octreotide vs. surgery. In addition, the group of previously treated patients was obviously selected to exclude patients who were cured with transsphenoidal surgery. Another potential caveat to the interpretation of our results is that the effect of partial surgical reduction in tumor mass on outcome is not known. Nevertheless, until partial debulking of a GH-secreting tumor is shown to be of specific benefit, the finding that octreotide is as effective in previously untreated patients as it is in previously treated patients suggests that primary treatment with octreotide may be as beneficial as the combination of surgery or radiation, and octreotide. If surgery is curative, it is clearly superior to medical therapy because it lowers GH and IGF-I immediately, alleviates symptoms, and eliminates the pituitary tumor. However, if it is unlikely that complete tumor removal will occur (as in the case of a macroadenoma or invasive tumor), and if there is no visual compromise, our data suggest that medical treatment with octreotide alone should be as effective biochemically and clinically as the combination of surgery followed by octreotide.
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Acknowledgments |
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Footnotes |
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Received February 5, 1998.
Revised May 22, 1998.
Accepted June 4, 1998.
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References |
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